Benzocycloheptenes, process for their production, pharmaceutical preparations that contain the latter as well as their use for the production of pharmaceutical agents

ABSTRACT

Benzocycloheptenes of formula (I), in which R 1 , R 2  and Y have the meanings that indicated herein, exhibit selective estrogenic activity on bones and are suitable for the production of pharmaceutical agents, especially for prophylaxis and therapy of osteoporosis:

This invention relates to benzocycloheptenes of general formula I

in which

-   -   R¹ and R², independently of one another, stand for a hydrogen        atom, a hydroxy group, an optionally substituted C₁-C₁₀ alkoxy        group, an optionally substituted C₁-C₁₀ alkanoyloxy group or an        optionally substituted C₇-C₁₅ aroyloxy group, and    -   SK stands for a side chain -A-B-Z,    -   whereby        -   A means a direct bond or an oxygen atom,        -   B means a straight-chain or branched-chain, optionally            substituted alkylene, alkenylene or alkinylene group with up            to 10 carbon atoms,        -   Z means a group -D-SO_(x)-E-G, an amino group —NR⁷R⁸ or a            substituent G,        -   in which        -   D means a direct bond or a group —NR³(R⁴—), R³ means a            straight-chain or branched-chain alkyl, alkenyl or alkinyl            group with up to 10 carbon atoms and R⁴ means a            straight-chain or branched-chain, optionally substituted            alkylene, alkenylene or alkinylene group with up to 10            carbon atoms, whereby the nitrogen atom also can be            incorporated in a 4- to 7-membered ring system,        -   the nitrogen atom can also be incorporated into a 4- to            7-membered ring system,        -   x means 0, 1 or 2,        -   E means a straight-chain or branched-chain, optionally            substituted alkylene, alkenylene or alkinylene group with up            to 10 carbon atoms,        -   G means a partially or completely fluorinated,            straight-chain or branched-chain alkyl group with up to 5            carbon atoms, an optionally substituted aryl or heteroaryl            radical, a carbamoyl radical —C(O)—NR⁵R⁶ with R⁵ and R⁶ in            the meaning of R⁷ and R⁸, a halogen atom or a hydrogen atom,        -   R⁷ and R⁸, independently of one another, mean a hydrogen            atom, a straight-chain or branched-chain, optionally            partially fluorinated alkyl, alkenyl or alkinyl radical with            up to 14 carbon atoms, which can be interrupted by one to            three heteroatoms —O— and —S— and groupings —NR⁹—, in which            R⁹ means a hydrogen atom or a C₁-C₃ alkyl radical, an aryl            or heteroaryl radical that is optionally substituted in one            or two places, a C₃-C₁₀ cycloalkyl radical that is            optionally substituted in one or two places, a C₄-C₁₅            cycloalkylalkyl radical that is optionally substituted in            one or two places, a C₇-C₂₀ aralkyl radical that is            optionally substituted in one or two places, a            heteroaryl-C₁-C₈ alkyl radical that is optionally            substituted in one or two places or an optionally            substituted aminoalkyl radical, a biphenylene radical or a            radical of formula —C(O)R¹⁰, in which R¹⁰ can have the            meanings that are indicated above for R⁷ or R⁸,        -   R⁷ and R⁸ with the nitrogen atom, to which they are bonded,            form a saturated or unsaturated heterocycle with 5 or 6            chain links, which optionally contains one or two additional            heteroatoms, selected from nitrogen, oxygen and sulfur, and            optionally is substituted, and in -A-B-Z, if A stands for an            oxygen atom and Z stands for G, G cannot be a hydrogen atom            or a halogen atom, or if A stands for an oxygen atom and Z            stands for an amino group —NR⁷R⁸, in which R⁷ and R⁸ in each            case mean a methyl group or together with the nitrogen atom            form a pyrrolidine ring, B has at least 3 carbon atoms.

As a C₁-C₁₀ alkoxy group R¹ or R², for example, a methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy,isopentoxy, neopentoxy, heptyloxy, hexyloxy or decyloxy group issuitable.

The alkanoyl groups that are contained in R¹ and R² of general formula Iare to contain 1 to 20 carbon atoms in each case, whereby formyl,acetyl, propionyl and isopropionyl groups are preferred.

Aroyl radicals R¹ or R² are primarily benzoates and benzoates that aresubstituted in the phenyl radical; they can also be the other aroyl andheteroaroyl radicals that are derived from the aryl radicals that areexplained in more detail below.

For B, primarily a straight-chain alkylene group with 1 to 6 carbonatoms is suitable.

As alkyl groups R³, R⁷ and R⁸, straight-chain or branched-chain alkylgroups with up to 10 carbon atoms can be considered, such as, forexample, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl.

The latter can have up to 3 unsaturations (double bonds and/or triplebonds).

Alkyl groups R³, R⁷ and R⁸ can be partially or completely fluorinated orsubstituted.

As a partially or completely fluorinated straight-chain or branchedC₁-C₁₀ alkyl group, for example, the trifluoromethyl group,pentafluoroethyl group, 2,2,2-trifluoroethyl group, 4,4,4-trifluorobutylgroup, 3,3,4,4,4-pentafluorobutyl group, 4,4,5,5,5-pentafluoropentylgroup or nonafluorobutyl group can be mentioned.

The latter can also have up to 3 unsaturations (double bonds and/ortriple bonds).

The C₁-C₃ alkyl radical that stands for R⁹ is a methyl, ethyl, propyl orisopropyl radical; the methyl radical is preferred.

For aryl radical R³ or R⁴ and G and the aryl radical within arylalkylradical R³ or R⁴, the following radicals that are optionally substitutedin one or more places can stand for:

-   -   a monocyclic, carbocyclic radical, for example the phenyl        radical;    -   a monocyclic, heterocyclic radical, for example the thienyl,        furyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl,        pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazanyl,        pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, triazolyl,        tetrazolyl radical, specifically all possible isomers relative        to the positions of the heteroatoms as well as the interface        sites to the sulfur atom in the side chain;    -   a condensed carbocyclic radical, for example the naphthyl or        phenanthrenyl radical;    -   a condensed radical, which consists of carbocyclic and        heterocyclic radicals, for example the benzofuranyl,        benzothienyl, benzimidazolyl, benzothiazolyl,        naphtho[2,3-b]thienyl, thianthrenyl, isobenzofuranyl, chromenyl,        xanthenyl, phenoxathiinyl, indolizinyl, isoindolyl, 3H-indolyl,        indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl,        quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl,        quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl,        acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, indolinyl,        isoindolinyl, imidazopyridyl, imidazopyrimidinyl or    -   a condensed polyheterocyclic system, for example        furo[2,3-b]pyrrole or thieno[2,3-b]furan.

As substituents to radicals B, G, R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R¹⁰ as wellas R³ together with R⁴, the substituents below are suitable, whereby theradicals can be substituted in one or more places, identically ordifferently, with these substituents:

Halogen atoms: fluorine, chlorine, bromine, iodine;

-   -   amino-, mono(C₁₋₈ alkyl)- or di(C₁₋₈ alkyl)amino, whereby both        alkyl groups are identical or different, especially methylamino        or ethylamino, dimethylamino, diethylamino or methylethylamino;        di(aralkyl)amino, whereby both-aralkyl groups are identical or        different;    -   hydroxyl groups;    -   free, esterified carboxyl groups or carboxyl groups that are        present in the form of a salt: esterified with a carboxycarbonyl        group, for example methoxycarbonyl or ethoxycarbonyl; as salt,        for example in the form of sodium or potassium salt;    -   alkyl groups with 1 to 8 carbon atoms, such as, for example, the        methyl, ethyl, n- or iso-propyl, n-, iso- or tert-butyl group,        optionally substituted with one or more halogen atoms, for        example with fluorine, such as the trifluoromethyl or        pentafluoroethyl group;    -   oxo, azido, cyano, nitro or formyl groups;    -   acyl groups such as acetyl, propionyl, butyryl, benzoyl;    -   acyloxy groups such as acetoxy, radicals of formula        —O—CO—(CH₂)_(n)—COOH with n=1 to 5;    -   C₁-C₄ alkoxy groups, such as, for example, methoxy, ethoxy,        propoxy, isopropoxy, butoxy;    -   alkylthio groups, for example methylthio, ethylthio, propylthio,        isopropylthio, butylthio, all optionally fluorinated,    -   carbamoyl groups;    -   alkenyl groups, for example vinyl, propenyl;    -   alkinyl groups, for example ethinyl, propinyl;    -   C₆-C₁₂ aryl groups, such as phenyl, furyl, thienyl, which in        turn can be substituted in one to three places.

As a cycloalkyl group for substituents R³ and R⁴, substituted andunsubstituted radicals with 3 to 10 carbon atoms are suitable; mainlythe cyclopropyl and cyclopentyl groups and, as an alkylcyclolalkylgroup, the methylcyclopropyl and methylcyclopentyl groups can bementioned.

The C₇-C₂₀ aralkyl radicals in R³ and R⁴ can contain up to 14 C atoms,preferably 6 to 10 C atoms, in the ring, and 1 to 8, preferably 1 to 4 Catoms in the alkyl chain.

As a heteroaryl part, a heteroaryl-C₁-C₈ alkyl radical in R³ and R⁴ hasone of the already mentioned heteroaryl radicals; the alkyl chain comeswith 1 to 8, preferably 1 to 4 C-atoms.

As aralkyl radicals, for example, benzyl, phenylethyl, naphthylmethyl,and napthylethyl are suitable, and as heteroarylalkyl radicals,furylmethyl, thienylethyl and pyridylpropyl are suitable.

The rings can be substituted in one or more places.

If R³ and R⁴ with the nitrogen atom, to which they are bonded, contain asaturated or unsaturated heterocycle with 5 or 6 chain links, whichoptionally contains one or two additional heteroatoms, selected fromnitrogen, oxygen and sulfur, this is especially a pyrrolidine,piperidine, morpholine or piperazine ring.

As substituents for aryl, heteroaryl, aralkyl and heteroarylalkylradicals, there can be mentioned especially a trifluoromethyl,pentafluoroethyl, trifluoromethylthio, methoxy, ethoxy, nitro, cyano,halogen (fluorine, chlorine, bromine, iodine), hydroxy, amino, mono(C₁₋₈alkyl) or di(C₁₋₈ alkyl)amino, whereby both alkyl groups are identicalor different, di(aralkyl)amino, whereby both aralkyl groups areidentical or different, or the 1-methoxyacetylamino radical.

The sulfur atom in the side chain can be present as a single sulfurbridge (sulfide), as a sulfone or sulfoxide.

Free hydroxy groups in the compounds of general formula I can bemodified functionally, for example by etherification or esterification;free hydroxy groups are preferred, however.

As ether and acyl radicals (protective groups), the radicals that areknown to one skilled in the art, such as., e.g., the methoxymethyl,methoxyethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl,trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl,tert-butyldiphenylsilyl, tribenzylsilyl, triisopropylsilyl, methyl,tert-butyl, benzyl, para-nitrobenzyl, para-methoxybenzyl, formyl,acetyl, propionyl, isopropionyl, butyryl, pivalyl, benzoyl radicals aresuitable. A survey is found in, e.g., “Protective Groups in OrganicSynthesis,” Theodora W. Green, John Wiley and Sons).

As specific side chains, in which A stands for an oxygen atom, there canbe mentioned

-   -   —O—(CH₂)₅S(CH₂)₃C₂F₅    -   —O—(CH₂)₅SO(CH₂)₃C₂F₅    -   —O—(CH₂)₅SO₂(CH₂)₃C₂F₅    -   —O—(CH₂)₂—N(CH₃)—(CH₂)₃—S—(CH₂)₃C₂F₅    -   —O—(CH₂)₂—N(CH₃)—(CH₂)₃—SO—(CH₂)₃C₂F₅    -   —O—(CH₂)₅S(CH₂)—C(O)N(CH₃)—(CH₂)₃CH₃    -   —O—(CH₂)₅SO(CH₂)—C(O)N(CH₃)—(CH₂)₃CH₃    -   —O—(CH₂)₂—NH(CH₂)OH    -   —O—(CH₂)₂—N(CH₃)—(CH₂)₂—SO(CH₂)—C(O)N(CH₃)—(CH₂)₃CH₃    -   —O—(CH₂)₂—N(CH₃)—(CH₂)₂—SO₂(CH₂)—C(O)N(CH₃)—(CH₂)₃CH₃    -   —O—(CH₂)₆S(CH₂)—C(O)N(CH₃)—(CH₂)₃CH₃    -   —O—(CH₂)₆SO(CH₂)—C(O)N(CH₃)—(CH₂)₃CH₃    -   —O—CH₃    -   —O—(CH₂)₅—F    -   —O—(CH₂)₄—F    -   —O—(CH₂)₃—F    -   —O—(CH₂)₂—F    -   —O—(CH₂)₅—Cl    -   —O—(CH₂)₄—Cl    -   —O—(CH₂)₃—Cl    -   —O—(CH₂)₂—Cl    -   —O—(CH₂)₆S(CH₂)₃C₂F₅    -   —O—(CH₂)₆SO(CH₂)₃C₂F₅    -   —O—(CH₂)₆SO(CH₂)-2-Pyridyl    -   —O—(CH₂)₅SO(CH₂)-2-Pyridyl    -   —O—(CH₂)₅S(CH₂)₂C₃F₇    -   —O—(CH₂)₂-1-Pyrrolidinyl    -   —O—(CH₂)₄S(CH₂)₃C₂F₅    -   —O—(CH₂)₄SO(CH₂)₃C₂F₅    -   —O—(CH₂)₄SO₂(CH₂)₃C₂F₅    -   —O—(CH₂)₄S(CH₂)-2-Pyridyl    -   —O—(CH₂)₄SO(CH₂)-2-Pyridyl    -   —O—(CH₂)₅S(CH₂)-2-Pyridyl    -   —O—(CH₂)₅SO(CH₂)-2-Pyridyl    -   —O—(CH₂)₆S(CH₂)-2-Pyridyl    -   —O—(CH₂)₆SO(CH₂)-2-Pyridyl    -   —O—(CH₂)₅S(CH₂)-2-Furyl    -   —O—(CH₂)₅SO(CH₂)-2-Furyl    -   —O—(CH₂)₅SO₂(CH₂)-2-Furyl    -   —O—(CH₂)₅S(CH₂)-2-Thienyl    -   —O—(CH₂)₅SO(CH₂)-2-Thienyl    -   —O—(CH₂)₅S(CH ₂—F    -   —O—(CH₂)₅SO(CH₂)₄—F    -   —O—(CH₂)₅S(CH₂)₃—CF₃    -   —O—(CH₂)₅SO(CH₂)₃—CF₃    -   —O—(CH₂)₅—N(CH₃)—(CH₂)₃—C₂F₅    -   —O—(CH₂)₅S(CH₂)-Phenyl    -   —O—(CH₂)₅SO(CH₂)-2-Phenyl    -   —O—(CH₂)₅S(CH₂)-p-Tolyl    -   —O—(CH₂)₅SO(CH₂)-p-Tolyl    -   —O—(CH₂)₅S(CH₂)-p-CF₃-Phenyl    -   —O—(CH₂)₅SO(CH₂)-p-CF₃-Phenyl    -   —O—(CH₂)₅S-Phenyl    -   —O—(CH₂)₅SO-Phenyl    -   —O—(CH₂)₅S-(p-Tolyl)    -   —O—(CH₂)₅SO-(p-Tolyl)    -   —O—(CH₂)₅S-(p-CF₃-Phenyl)    -   —O—(CH₂)₅SO-(p-CF₃-Phenyl)    -   —O—(CH₂)₂—N(CH₃)₂

As side chains, in which A stands for a direct bond, for example, thefollowing are suitable (DE 1 98 06 357.1)

-   -   —(CH₂)₅N(CH₃)(CH₂)₃C₂F₅    -   —(CH₂)₅N(CH₃)(CH₂)₆C₂F₅    -   —(CH₂)₅N(CH₃)(CH₂)₇C₂F₅    -   —(CH₂)₅N(CH₃)(CH₂)₈C₂F₅    -   —(CH₂)₆N(CH₃)(CH₂)₆C₂F₅    -   —(CH₂)₆N(CH₃)(CH₂)₇C₂F₅    -   —(CH₂)₆N(CH₃)(CH₂)₈C₂F₅    -   —(CH₂)₅N(CH₃)(CH₂)₂C₄F₉    -   —(CH₂)₅N(CH₃)(CH₂)₃C₆F₁₃    -   —(CH₂)₅N(CH₃)(CH₂)₃C₈F₁₇    -   —(CH₂)₅N(CH₃)(CH₂)₆C₄F₉    -   —(CH₂)₅N(CH₃)(CH₂)₆C₆F₁₃    -   —(CH₂)₅N(CH₃)(CH₂)₆C₈F₁₇    -   —(CH₂)₅N(CH₃)H    -   —(CH₂)₅N(CH₃)(CH₂)₉H    -   —(CH₂)₅-1-Pyrrolidinyl    -   —(CH₂)₉S(CH₂)₃C₂F₅    -   —(CH₂)₉SO(CH₂)₃C₂F₅    -   —(CH₂)₉SO₂(CH₂)₃C₂F_(5.)

In addition, the side chains of general partial formula

are suitablewhereby

-   -   a is 4, 5 or 6,    -   b is 0, 1 or 2,    -   c is 0, 1 or 2,    -   R⁵ is a hydrogen atom or a C₁₋₅ alkyl group,    -   R⁶ and R⁷ are each a hydrogen atom, or    -   R⁵ and R⁶ together are an alkylene group —(CH₂)_(d)— with d=2,        3, 4 or 5, and R⁷ is a hydrogen atom or    -   R⁵ and R⁷ together are an alkylene group —(CH₂)_(e)— with e=2, 3        or 4 and R⁶ is a hydrogen atom, and    -   U is an unsubstituted ethyl radical or an ethyl radical that is        fluorinated in one to five places, or    -   the terminal substituent —(CH₂)₃—U in the side chain is replaced        by an optionally substituted aryl or heteroaryl radical,        which is bonded directly or via a mono-, di- or trimethylene        group to the sulfur atom,        and of the latter in turn especially the side chains    -   —(CH₂)₅N(CH₃)(CH₂)₃S(CH₂)₃C₂F₅ and    -   —(CH₂)₅N(R⁵)(CHR⁶)CH₂S(CH₂)₃C₂F₅ with R⁵+R⁶=—(CH₂)₃—.

For the purposes of this invention, the preferred compounds are

-   -   (4,4,5,5,5-Pentafluoropentyl)-{5-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentyl}-sulfide    -   (4,4,5,5,5-pentafluoropentyl)-{5-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentyl}-sulfoxide    -   methyl-[3-(4,4,5,5,5-pentafluoropentylthio)-propyl]-{2-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-ethyl}-amine    -   methyl-[3-(4,4,5,5,5-pentafluoropentylsulfinyl)-propyl]-{2-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-ethyl}-amine    -   S-{5-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentyl}-thioacetate    -   N-butyl-N-methyl-2-{5-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentylthio}-acetamide    -   N-butyl-N-methyl-2-{5-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentanesulfinyl}-acetamide    -   5-{4-[5-(4,4,5,5,5-pentafluoro-pentylthio)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol    -   5-{4-[5-(4,4,5,5,5-pentafluoro-pentanesulfinyl)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol    -   5-[4-(2-{methyl-[3-(4,4,5,5,5-pentafluoro-pentanesulfinyl)-propyl]-amino}-ethoxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol    -   5-[4-(2-{methyl-[3-(4,4,5,5,5-pentafluoro-pentylthio)-propyl]-amino}-ethoxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol    -   N-butyl-N-methyl-2-{5-[4-(2-hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentylthio}-acetamide    -   5-{4-[5-(4,4,5,5,5-pentafluoro-pentanesulfonyl)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol    -   N-butyl-N-methyl-2-{5-[4-(2-hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentanesulfinyl}-acetamide    -   N-butyl-2-[2-({2-[4-(2-hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-ethyl}-methyl-amino)-ethanesulfinyl]-N-methyl-acetamide    -   N-butyl-2-[2-({2-[4-(2-hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-ethyl}-methyl-amino)-ethanesulfonyl]-N-methyl-acetamide    -   6-(4-hydroxy-phenyl)-5-{4-[5-(4,4,5,5,5-pentafluoro-pentanesulfonyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol    -   N-butyl-2-{6-[4-(2-hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-hexanesulfinyl}-N-methyl-acetamide    -   N-butyl-2-{6-[4-(2-hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-hexylthio}-N-methyl-acetamide    -   6-(4-hydroxy-phenyl)-5-{4-[5-(4,4,5,5,5-pentafluoropentylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol    -   6-(4-hydroxy-phenyl)-5-{4-[5-(4,4,5,5,5-pentafluoropentane-sulfinyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol    -   5-{4-[4-(4,4,5,5,5-pentafluoro-pentylthio)-butyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol    -   6-phenyl-5-{4-[4-(pyridin-2-ylmethylthio)-butyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol    -   6-phenyl-5-{4-[5-(pyridin-2-ylmethylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol    -   6-phenyl-5-{4-[6-(pyridin-2-ylmethylthio)-hexyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol    -   5-{4-[4-(4,4,5,5,5-pentafluoro-pentanesulfinyl)-butyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol    -   6-phenyl-5-{4-[4-(pyridin-2-ylmethanesulfinyl)-butyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol    -   5-{4-[6-(4,4,5,5,5-pentafluoro-pentylthio)-hexyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol    -   5-{4-[6-(4,4,5,5,5-pentafluoro-pentanesulfinyl)-hexyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol    -   6-phenyl-5-{4-[6-(pyridin-2-ylmethanesulfinyl)-hexyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol    -   6-phenyl-5-{4-[5-(pyridin-2-ylmethanesulfinyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol    -   5-{4-[5-(furan-2-ylmethylthio)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol    -   6-phenyl-5-{4-[5-(thien-2-ylmethylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol    -   5-{4-[5-(furan-2-ylmethanesulfinyl)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol    -   5-{4-[5-(furan-2-ylmethanesulfonyl)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol    -   6-phenyl-5-{4-[5-(thien-2-ylmethanesulfonyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol    -   6-phenyl-5-{4-[5-(thien-2-ylmethanesulfinyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol    -   5-{4-[5-(3,3,4,4,5,5,5-heptafluoro-pentylthio)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol    -   5-{4-[2-(2-hydroxy-ethylamino)-ethoxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol    -   5-{4-[5-(4-fluoro-butylthio)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol    -   5-{4-[5-(4-fluoro-butanesulfinyl)-pentyloxy]-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol    -   6-phenyl-5-{4-[5-(4,4,4-trifluoro-butylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol    -   6-phenyl-5-{4-[5-(4,4,4-trifluoro-butanesulfinyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol    -   5-(4-{5-[methyl-(4,4,5,5,5-pentafluoropentyl)-amino]-pentyloxy}-phenyl)-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol    -   5-[4-(5-benzylthio-pentyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol    -   5-[4-(5-benzylsulfinyl-pentyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol    -   5-{4-[5-(4-methyl-benzylthio)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol    -   5-{4-[5-(4-methyl-benzylsulfinyl)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol    -   6-phenyl-5-{4-[5-(4-trifluoromethyl-benzylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol    -   6-phenyl-5-{4-[5-(4-trifluoromethyl-benzylsulfinyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol    -   6-phenyl-5-[4-(5-phenylthio-pentyloxy)-phenyl]-8,9-dihydro-7H-benzocyclohepten-2-ol    -   6-phenyl-5-[4-(5-phenylsulfinyl-pentyloxy)-phenyl]-8,9-dihydro-7H-benzocyclohepten-2-ol    -   6-phenyl-5-[4-(5-phenylsulfonyl-pentyloxy)-phenyl]-8,9-dihydro-7H-benzocyclohepten-2-ol    -   5-{4-[5-(4-tert-butyl-phenylthio)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol    -   5-{4-[5-(4-tert-butyl-phenylsulfinyl)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol    -   5-{4-[5-(4-tert-butyl-phenylsulfonyl)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol    -   6-phenyl-5-{4-[5-(4-trifluoromethyl-phenylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol    -   6-phenyl-5-{4-[5-(4-trifluoromethyl-phenylsulfinyl)-pentyloxy]-phenyl}-8,9-dihydroxy-7H-benzocyclohepten-2-ol    -   6-phenyl-5-{4-[5-(4-trifluoromethyl-phenylsulfonyl)-pentyloxy]-phenyl}-8,        9-dihydro-7H-benzocyclohepten-2-ol.

In addition to these compounds of general formula I, if a nitrogen atomis contained in side chain SK, this invention also relates to theirphysiologically compatible addition salts with organic and inorganicacids, these compounds of general formula I including the pharmaceuticalpreparations that contain addition salts as well as their use for theproduction of pharmaceutical agents.

Inorganic and organic acids, as they are known to one skilled in the artfor the formation of physiologically compatible salts, are suitable forthe formation of acid addition salts. As addition salts with acids,especially hydrochlorides, hydrobromides, acetates, citrates, oxalates,tartrates and the methanesulfonates can be mentioned.

The compounds of general formula I represent compounds with strongantiestrogenic activity.

The compounds according to the invention are selective estrogens, whoseaction occurs in a tissue-selective manner. The estrogenic action occursin particular on bones. No estrogenic action or only a slight estrogenicaction occurs in the uterus and in the liver, however.

The compounds can also have antiestrogenic activity, which can bedetected, for example, in an anti-uterus growth test or in tumor models.Compounds with such a profile have recently been designated as SelectiveEstrogen Receptor Modulators (SERMs) (Structure-Activity Relationshipsof Selective Estrogen Receptor Modulators: Modifications to the2-Arylbenzothiophene Core of Raloxifene, T. A. Grese et al., J. Med.Chem. 1997, 40, 146-167).

The most prominent representative of this compound class is raloxifene,which is now allowed as a medication for the prevention and thetreatment of postmenopausal osteoporosis.

Compounds with antiestrogenic properties, i.e., substances withinhibiting actions relative to estrogens, have already been describedextensively. In this case, these are compounds both with a steroidal andwith a non-steroidal skeleton.

The tamoxifen that became known for the first time from BE 637, 389,(Z)-2-[4-(1,2-diphenyl-1-butenyl)-phenoxy]-N,N-dimethylethylamine, hasbeen used for breast cancer therapy longer than antiestrogen.

Raloxifene,6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2piperidinoethoxy)benzoyl]benzo[b]-thiophene,and its hydrochloride can be used for treatment and prophylaxis ofosteoporosis (EP 0 584 952 B1).

The steroid derivative7α-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-n-nonyl]-estra-1,3,5(10)-triene-3,17β-diol(EP A 0 138 504, page 58, penultimate compound) that became known fromEP A 0 138 504 B1 is currently under clinical development forhormone-dependent tumors (breast cancer).

Pharmaceutical compositions, which contain sex steroid inhibitors andwhich have a steroidal skeleton that has a 7α-side chain in the case ofthe simultaneous presence of at least one additional substituent in 14-,15- or 16-position, are the subject of EP-A 0 376 576. This patentapplication also relates to non-steroidal, antiestrogenic compounds,i.a., the compound EM 800. This compound was described originally as apure antiestrogen; it has now been found, however, that this compoundalso has a clear partial estrogenic action.

The estrogen agonists and antagonists that became known from WO 96/21656are, i.a., benzocyclopentane, hexane and heptane derivatives, which inthe aromatic portion carry a hydroxy group, a nitrogen aromatic compoundon carbon atom 5 or a phenyl radical that is provided with a side chainin 4-position and a phenyl radical that optionally has a side chain oncarbon atom 6, i.a. Compounds with an unsaturation in the slightlycondensed structural part are not disclosed there. Actually, merelybenzocyclohexane derivatives are described.

Some compounds with a benzocycloheptene basic structure are found invarious publications (Mol. Pharmacol. 1991, 39: 421-428; J. Med. Chem.,1986, 29, 2053-2059; J. Med. Chem., 1988, 31, 1316-1326). Thesecompounds have in 4-position the phenyl radical that is bonded to carbonatom 5, a methoxy group, a 2-(dimethylamino)ethoxy group or a2-(1-pyrrolidinyl)ethoxy group. It is not said of these compounds thatthey are selective estrogens.

PHARMACOLOGICAL STUDY OF THE COMPOUNDS ACCORDING TO THE INVENTION

The influence of the compounds according to the invention on the uteruswas studied in the uterus growth test (estrogenic action) and in theanti-uterus growth test (antiestrogenic action), both performed oninfant rats.

Estrogenic/Antiestrogenic Action in Vivo

Uterus Growth Test on Infant Rats (n=5 Animals/Group)

In infant animals, both uterus and vagina show a weight increase that isdependent on the estrogenic activity in their treatment with anestrogenically active substance. In the uterus, under estrogenic action,this results, moreover, in a proliferation and level increase of theluminal epithelium. Immature, normal rats (body weight 40-50 g) receivethe substance s.c. over 3 days (d1-d3). On day 4 (d4), the animals aresacrificed with CO₂. The uteri are prepared outside and weighed. A pieceof the uterus, preferably a uterine horn, is set in formaldehyde forhistological evaluation and embedded in paraffin. The stimulation of theorgan weights (relative to mg/100 g of body weight) as well as theepithelial level are indicated in percentage stimulation in comparisonto the reference compound 17β-estradiol. (Substitution dose E₂ 0.3μg/animal).

The compounds according to the invention have no effect or an onlyslightly stimulating effect on the uterus.

Antiuterus Growth Test on Infant Rats (n=5 Animals/Group)

The uterus of infant estrogen-substituted rats can be used as a testmodel to detect a direct action of substances with antiestrogenicproperties. The parameter of the estrogen action is the uterus growththat is induced by estradiol in infant rats, which is inhibited by thesimultaneous administration of a substance with antiestrogenic action.

The test substances are treated s.c. on 3 successive days (d1-d3) incombination with a substitution dose of 0.3 μg/animal/day of17β-estradiol. As a positive control, 17β-estradiol is used alone; as anegative control, the vehicle group is used. On day 4 (d4), the animalsare sacrificed, uteri and vaginae are prepared outside and weighed. Theorgan weights are calculated in mg/100 g of body weight, then the meanvalue and the standard deviation for each dosage is calculated. Theinhibition of the uterus or vaginal growth that is induced by17β-estradiol is indicated as inhibition in %.

The compounds according to the invention for the most part show aclearly pronounced inhibition of the uterus growth that is induced by17β-estradiol.

Thus with respect to their action on the uterus, the compounds accordingto the invention are superior to the compounds of the prior art for thepurposes of this invention to the extent that they have less or even noestrogenic action on this organ.

Bone Studies

Method

3-month-old female rats are ovariectomized and treated once daily withthe test compound immediately after the operation for 28 days. Theadministration is carried out subcutaneously in peanut oil/ethanol. Theanimals are sacrificed on the day after the last administration, andtibia as well as uteri are removed. The uteri are weighed, set andworked up for histological studies. The determination of bone density iscarried out ex vivo on prepared long bones using pQCT (quantitativecomputer tomography). The measurements are carried out at a distance of4-6 mm from the ball of the joint of the proximal tibia.

The density of the trabecular bone in the measured area is reduced bythe ovariectomy from about 400 mg of Ca²⁺/cm³ to about 300 mg ofCa²⁺/cm³. The degradation of bone density is prevented or inhibited bythe treatment with a compound of general formula I according to thisinvention (dosages of 0.1-100 μg/animal/day). The bone density wasmeasured at the proximal tibia.

With respect to their bone-protective action, the compounds according tothe invention have an action that is comparable to the compounds of theprior art in the case of simultaneously weakened or absent uterotrophicestrogenic action.

Thus for the purpose of a selective action on the bone with respect to aweakened action on the uterus, the compounds according to the inventionare more greatly dissociated than the compounds of the prior art.

The invention also relates to pharmaceutical preparations, which containat least one compound of general formula I (or physiologicallycompatible addition salts with organic and inorganic acids thereof), andthe use of these compounds for the production of pharmaceutical agents,especially for the indications below.

The compounds can be used both after oral and parenteral administrationfor the following indications:

Alleviation of the symptoms of male menopause and female menopause,i.e., for male and female hormone replacement therapy (HRT),specifically both for prevention and for treatment; for treatment ofsymptoms accompanying a dysmenorrhea; treatment of dysfunctional uterinebleeding; treatment of acne; prevention and treatment of cardiovasculardiseases; treatment of hypercholesteremia and hyperlipemia; preventionand treatment of arteriosclerosis; for inhibition of the proliferationof arterial smooth muscle cells; for treatment of the respiratorydistress syndrome in newborn children; treatment of primary pulmonaryhigh blood pressure; for prevention and treatment of osteoporosis(Black, L. J.; Sato, M.; Rowley, E. R.; Magee, D. E.; Bekele, A.;Williams, D. C.; Cullinan, G. J.; Bendele, R.; Kauffman, R. F.; Bensch,W. R.; Frolik, C. A.; Termine, J. D. and Bryant, H. U.: Raloxifene [LY139481 HCl] Prevents Bone Loss and Reduces Serum Cholesterol withoutCausing Uterine Hypertrophy in Ovariectomized Rats; J. Clin. Invest. 93:63-69, 1994); for prevention of bone loss in postmenopausal women, inwomen who have had hysterectomies or in women who were treated with LHRHagonists or antagonists; inhibition of spermatic maturation; treatmentof rheumatoid arthritis; for prevention of Alzheimer's disease;treatment of endometriosis; treatment of myomas; treatment of myomas andendometriosis in combination with LHRH analogues; treatment ofhormone-dependent tumors, e.g., breast cancer, treatment of prostaticdiseases.

In addition, the compounds according to the invention are suitable basedon their pharmacological profile both for male and for femalecontraception.

The compounds can also be used in combination with the natural vitaminD3 or with calcitriol analogues for bone degradation or as supportingtherapies to therapies that cause bone mass loss (for example therapywith glucocorticoids, chemotherapy).

Finally, the compounds of general formula I can be used in connectionwith progesterone receptor antagonists or in connection with pureestrogens, specifically especially for use in hormone replacementtherapy and for treatment of gynecological disorders and for femalebirth control.

A therapeutic product that contains an estrogen and a pure antiestrogenfor simultaneous, sequential or separate use of the selective estrogentherapy of perimenopausal or postmenopausal conditions is alreadydescribed in EP-A 0 346 014.

The amount of a compound of general formula I that is to be administeredfluctuates within a wide range and can cover any effective amount. Basedon the condition to be treated and the type of administration, theamount of administered compound can be 0.01-10 mg/kg of body weight,preferably 0.1-5 mg/kg of body weight, per day.

In humans, this corresponds to a dose of 0.8 to 800 mg, preferably 8 to400 mg, daily.

A dosage unit contains, according to the invention, 0.4 to 400 mg of oneor more compounds of general formula I.

The compounds according to the invention and the acid addition salts aresuitable for the production of pharmaceutical compositions andpreparations. The pharmaceutical compositions or pharmaceutical agentscontain as active ingredient one or more of the compounds according tothe invention or their acid addition salts, optionally mixed with otherpharmacologically or pharmaceutically active substances. The productionof the pharmaceutical agents is carried out in a known way, whereby theknown and commonly used pharmaceutical adjuvants and other commonly usedvehicles and diluents can be used.

As such vehicles and adjuvants, for example, those are suitable that arerecommended or indicated in the following bibliographic references asadjuvants for pharmaceutics, cosmetics and related fields: UllmansEncyklopädie der technischen Chemie [Ullmans Encyclopedia of TechnicalChemistry], Volume 4 (1953), pages 1 to 39; Journal of PharmaceuticalSciences, Volume 52 (1963), pages 918 ff. issued by Czetsch-Lindenwald,Hilfsstoffe für Pharmazie und angrenzende Gebiete [Adjuvants forPharmaceutics and Related Fields]; Pharm. Ind., Issue 2, 1961, pages 72and ff.: Dr. H. P. Fiedler, Lexikon der Hilfsstoffe für Pharmazie,Kosmetik und angrenzende Gebiete [Dictionary of Adjuvants forPharmaceutics, Cosmetics and Related Fields], Cantor KG, Aulendorf inWürttemberg 1971.

The compounds can be administered orally or parenterally, for exampleintraperitoneally, intramuscularly, subcutaneously or percutaneously.The compounds can also be implanted in the tissue.

For oral administration, capsules, pills, tablets, coated tablets, etc.are suitable. In addition to the active ingredient, the dosage units cancontain a pharmaceutically compatible vehicle, such as, for example,starch, sugar, sorbitol, gelatin, lubricant, silicic acid, talc, etc.

For parenteral administration, the active ingredients can be dissolvedor suspended in a physiologically compatible diluent. As diluents, oilsare very frequently used with or without the addition of a solubilizer,a surfactant, a suspending agent or an emulsifier. Examples of oils thatare used are olive oil, peanut oil, cottonseed oil, soybean oil, castoroil and sesame oil.

The compounds can also be used in the form of a depot injection or animplant preparation, which can be formulated in such a way that adelayed release of active ingredient is made possible.

As inert materials, implants can contain, for example, biodegradablepolymers or synthetic silicones such as, for example, silicone rubber.

In addition, the active ingredients can be added for percutaneousadministration, for example, to a patch.

For the production of intravaginal systems (e.g., vaginal rings) orintrauterine systems (e.g., pessaries, coils, IUDs, Mirena®) that areloaded with active compounds of general formula I for localadministration, various polymers are suitable, such as, for example,silicon polymers, ethylene vinyl acetate, polyethylene or polypropylene.

To achieve better bioavailability of the active ingredient, thecompounds can also be formulated as cyclodextrin clathrates. For thispurpose, the compounds are reacted with α-, β- or γ-cyclodextrin orderivatives of the latter (PCT/EP95/02656).

According to the invention, the compounds of general formula I can alsobe encapsulated with liposomes.

The compounds of general formula I according to the invention areproduced as described in the examples. By an analogous procedure usingreagents that are homologous to the reagents that are described in theexamples; all compounds of general formula I can be obtained.

Etherification and/or esterification of free hydroxy groups is carriedout according to the methods that are common to one skilled in the art.

The compounds of general formula I, in which A stands for a direct bond,can be obtained, for example, analogously to the processes that aredescribed in WO 98/07740 and DE 1 98 06 357.1. To introduce side chainSK, first the 4-hydroxy group of the phenyl radical in 5-position of thestarting product is converted into a trifluoromethylsulfonyloxy groupand then palladium-catalyzed, and an alkylation on the phenyl radical iscarried out to introduce terminally functionalized radical B (J. Org.Chem., 58; 8; 1993, pp. 2201-2208; Tetrahedron Lett. 28: 21; 1987, pp.2387-2388). The further processing for the creation of complete sidechain SK is then carried out as described in WO 98/07740 or DE 1 98 06357.1.

EXAMPLES Example 1(4,4,5,5,5-Pentafluoropentyl)-{5-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentyl}-sulfidea)9-[4-(5-Chloropentyloxy)-phenyl]-8-phenyl-6,7-dihydro-5H-benzocycloheptene

A suspension of 3.0 g of4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenol [RaymondMcCague, Reiko Kuroda, Guy Leclerq, Susanna Stoessel, J. Med. Chem. (29)10 1986 pp. 2053-2059] in 51 ml of acetonitrile is stirred with 1.68 gof potassium carbonate and 1.49 ml of 1-bromo-5-chloropentane for 9hours at 100° C. Then, it is added to water, extracted three times withethyl acetate, washed neutral, dried on sodium sulfate, concentrated byevaporation in a vacuum and chromatographed on silica gel withhexane/ethyl acetate. 3.52 g of9-[4-(5-chloropentyloxy)-phenyl]-8-phenyl-6,7-dihydro-5H-benzocyclohepteneis obtained as crystals with a melting point of 118-120° C.

b)9-[4-(5-Iodopentyloxy)-phenyl]-8-phenyl-6,7-dihydro-5H-benzocycloheptene

A solution of 3.32 g of9-[4-(5-chloropentyloxy)-phenyl]-8-phenyl-6,7-dihydro-5H-benzocycloheptenein 120 ml of ethylmethylketone is stirred with 4.5 g of sodium iodidefor 9.5 hours at a bath temperature of 100° C. Then, it is added towater, extracted three times with ethyl acetate, washed neutral, driedon sodium sulfate and concentrated by evaporation in a vacuum. 4.02 g of9-[4-(5-iodopentyloxy)-phenyl]-8-phenyl-6,7-dihydro-5H-benzocyclohepteneis obtained as crystals with a melting point of 104-106° C.

c)(4,4,5,5,5-Pentafluoropentyl)-{5-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentyl}-sulfide

A solution of 2.35 g of 4,4,5,5,5-pentafluoropentylthioacetate in 12 mlof methanol is stirred with 1.88 ml of a 30% methanolic sodium methylatesolution at room temperature for 0.5 hour. This solution is added indrops to a suspension of 4.0 g of9-[4-(5-iodopentyloxy)-phenyl]-8-phenyl-6,7-dihydro-5H-benzocycloheptenein 44 ml of methanol and 44 ml of diethyl ether, and it is stirred for 6hours at room temperature. Then, the methanol is concentrated byevaporation in a vacuum, added to water, extracted three times withethyl acetate, washed neutral, dried on sodium sulfate and concentratedby evaporation in a vacuum. 4.5 g(4,4,5,5,5-pentafluoropentyl)-{5-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentyl}-sulfideis obtained as crystals with a melting point of 84-85° C.

Example 2(4,4,5,5,5-Pentafluoropentyl)-{5-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentyl}-sulfoxide

A solution of 4.4 g of(4,4,5,5,5-pentafluoropentyl)-{5-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentyl}-sulfidein 130 ml of methanol is mixed at room temperature with 7.1 ml of waterand 1.86 g of sodium periodate, and it is stirred for 24 hours. then, itis evaporated to the dry state in a vacuum, taken up withdichloromethane/water, washed with water, dried on sodium sulfate andconcentrated by evaporation in a vacuum and chromatographed on silicagel with dichloromethane/acetone. 3.6 g of(4,4,5,5,5-pentafluoropentyl)-{5-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentyl}-sulfoxideis obtained as colorless crystals with a melting point of 114-116° C.

Methyl-[3-(4,4,5,5,5-pentafluoropentylthio)-propyl]-{2-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-ethyl}-aminea)9-[4-(2-Chloroethoxy)-phenyl]-8-phenyl-6,7-dihydro-5H-benzocycloheptene

A suspension of 3.0 g of4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenol {RaymondMcCague, Reiko Kuroda, Guy Leclerq, Susanna Stoessel, J. Med. Chem. (29)10 1986 pp. 2053-2059] in 51 ml of acetonitrile is stirred wtih 1.68 gof potassium carbonate and 0.95 ml of 1-bromo-2-chloroethane for 28hours at a bath temperature of 100° C. Then, it is added to water,extracted three times with ethyl acetate, washed neutral, dried onsodium sulfate, concentrated by evaporation in a vacuum andchromatographed on silica gel with hexane/ethyl acetate. 2.93 g of9-[4-(2-chloroethoxy)-phenyl]-8-phenyl-6,7-dihydro-5H-benzocyclohepteneis obtained as crystals with a melting point of 171-172° C.

b) 9-[4-(2-Iodoethoxy)-phenyl]-8-phenyl-6,7-dihydro-5H-benzocycloheptene

A solution of 2.73 g of9-[4-(2-chloroethoxy)-phenyl]-8-phenyl-6,7-dihydro-5H-benzocycloheptenein 110 ml of ethylmethylketone is stirred with 4.11 g of sodium iodidefor 28 hours at a bath temperature of 100° C. Then it is added to water,extracted three times with ethyl acetate, washed neutral, dried onsodium sulfate, concentrated by evaporation in a vacuum andchromatographed on silica gel with hexane/ethyl acetate. 2.60 g of9-[4-(5-iodoethoxy)-phenyl]-8-phenyl-6,7-dihydro-5H-benzocycloheptene isobtained as crystals with a melting point of 154-156° C.

c)Methyl-{2-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-ethyl}-amine

A solution of 2.2 g of9-[4-(5-iodoethoxy)-phenyl]-8-phenyl-6,7-dihydro-5H-benzocycloheptene in55 ml of dimethylformamide and 1.1 ml of triethylamine is stirred with4.4 ml of a 40% aqueous methylamine solution of 1 hour at a bathtemperature of 80° C. Then, it is added to saturated common saltsolution, extracted three times with ethyl acetate, washed neutral,dried on sodium sulfate, concentrated by evaporation in a vacuum andchromatographed on silica gel with hexane/ethyl acetate. 0.9 g ofmethyl-{2-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-ethyl}-amineis obtained as crystals with a melting point of 165-167° C.

d)Methyl-[3-(4,4,5,5,5-pentafluoropentylthio)-propyl]-{2-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-ethyl}-amine

A solution of 0.9 g ofmethyl-{2-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-ethyl}-amineand 0.4 g of potassium carbonate in 14 ml of dimethylformamide is mixeddrop by drop with a solution of 1.0 g of1-iodo-3-(4,4,5,5,5-pentafluoropentylthio)-propane in 2 ml ofdimethylformamide, and it is stirred for 2 hours at a bath temperatureof 80° C. Then, it is added to water, extracted three times with ethylacetate, washed neutral, dried on sodium sulfate and concentrated byevaporation in a vacuum. 570 mg ofmethyl-[3-(4,4,5,5,5-pentafluoropentylthio)-propyl]-{2-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-ethyl}-amineis obtained as an oil.

Example 4Methyl-[3-(4,4,5,5,5-pentafluoropentylsulfinyl)-propyl]-{2-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-ethyl}-amine

Analogously to what is described in Example 2, 0.55 g ofmethyl-[3-(4,4,5,5,5-pentafluoropentylthio)-propyl]-{2-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-ethyl}-amineis oxidized, and 334 mg ofmethyl-[3-(4,4,5,5,5-pentafluoropentylsulfinyl)-propyl]-{2-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-ethyl}-amineis obtained as crystals with a melting point of 74-77° C.

Example 5S-{5-[4-(6-Phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentyl}-thioacetate

A solution of 8.0 g of9-[4-(5-iodopentyloxy)-phenyl]-8-phenyl-6,7-dihydro-5H-benzocycloheptenein 170 ml of acetone is stirred with 5.36 g of potassium thioacetate for2.5 hours at room temperature. then, it is added to water, extractedthree times with ethyl acetate, washed neutral, dried on sodium sulfate,concentrated by evaporation in a vacuum and chromatographed on silicagel with hexane/ethyl acetate. 6.5 g ofS-{5-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy}-pentyl}-thioacetateis obtained as crystals with a melting point of 118-120° C.

Example 6N-Butyl-N-methyl-2-{5-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentylthio}-acetamide

A solution of 1 g ofS-{5-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentyl}-thioacetatein 15 ml of methanol and 10 ml of tetrahydrofuran is stirred with 0.42ml of a 30% methanolic sodium methylate solution for 0.5 hour at roomtemperature, and after 0.5 ml of 2-bromo-N-butyl-N-methyl-acetamine isadded, it is stirred for another hour. Then, it is added to water,extracted three times with ethyl acetate, washed neutral, dried onsodium sulfate, concentrated by evaporation in a vacuum andchromatographed on silica gel with hexane/ethyl acetate. 593 mg ofN-butyl-N-methyl-2-{5-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentylthio}-acetamide is obtained as an oil.

Example 7N-Butyl-N-methyl-2-{5-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentanesulfinyl}-acetamide

Analogously to what is described in Example 2, 0.4 g ofn-butyl-N-methyl-2-{5-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentylthio}-acetamideis oxidized, and 301 mg ofN-butyl-N-methyl-2-{5-[4-(6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentanesulfinyl}-acetamideis obtained as crystals with a melting point of 120-121° C.

Example 85-{4-[5-(4,4,5,5,5-Pentafluoro-pentylthio)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ola)2-Benzyloxy-5-(4-methoxyphenyl)-6,7,8,9-tetrahydro-benzocyclohepten-5-ol

A suspension of 14.57 g of magnesium chips in 150 ml of diethyl ether ismixed drop by drop with a solution of 88 ml of 4-bromanisole in 100 mlof diethyl ether so that the reaction mixture is refluxed withoutexternal heat supply. After the addition is completed, it is allowed tocool to room temperature, and a solution of 35.2 g of2-benzyloxy-6,7,8,9-tetrahydro-benzocyclohepten-5-one [Lal, B. et al.,J. Med. Chem. (15) 1972 pp. 23-27] in 150 ml of diethyl ether is slowlyadded and stirred for another 4.5 hours at room temperature. Then, it iscooled to 0° C., and saturated ammonium chloride solution is added.Then, it is added to water, extracted three times with ethyl acetate,washed neutral, dried on sodium sulfate, concentrated by evaporation ina vacuum and chromatographed on silica gel with hexane/ethyl acetate. 37g of2-benzyloxy-5-(4-methoxyphenyl)-6,7,8,9-tetrahydro-benzocyclohepten-5-ylis obtained as crystals with a melting point of 112-114° C.

b) 2-Benzyloxy-5-(4-methoxyphenyl)-8,9-dihydro-7H-benzocycloheptene

A suspension of 35.8 g of2-benzyloxy-5-(4-methoxy-phenyl)-6,7,8,9-tetrahydrobenzocyclohepten-5-olin 1 1 of methanol is stirred with 32 ml of concentrated hydrochloricacid for 3 hours at room temperature. Then, it is neutralized withsodium bicarbonate solution, concentrated by evaporation in a vacuum to300 ml, added to water, extracted three times with ethyl acetate, washedneutral, dried on sodium sulfate and concentrated by evaporation in avacuum. 34 g of2-benzyloxy-5-(4-methoxyphenyl)-8,9-dihydro-7H-benzocycloheptene isobtained as crystals with a melting point of 76-78° C.

c)2-Benzyloxy-6-bromo-5-(4-methoxyphenyl)-8,9-dihydro-7H-benzocycloheptene

A solution of 34 g of2-benzyloxy-5-(4-methoxyphenyl)-8,9-dihydro-7H-benzocycloheptene in 310ml of dichloromethane is mixed at 0° C. in portions with 29 g ofpyridinium hydrobromide perbromide for 1 hour, and it is stirred for 0.5hour at 0° C. Then, 200 ml of an aqueous sodium hydrogen sulfitesolution is added at 0° C., added to water, extracted twice withdichloromethane, washed with sodium bicarbonate and common saltsolution, dried on sodium sulfate, concentrated by evaporation in avacuum and chromatographed on silica gel with hexane/ethyl acetate. 35 gof2-benzyloxy-6-bromo-5-94-methoxyphenyl)-8,9-dihydro-7H-benzocyclohepteneis obtained as crystals with a melting point of 141-143° C.

d)2-Benzyloxy-5-(4-methoxyphenyl)-6-phenyl-8,9-dihydro-7H-benzocycloheptene

A suspension of 22.32 g of zinc chloride in 60 ml of tetrahydrofuran ismixed at room temperature with 91.2 ml of a 1.8 M phenyllithium solutionwithin three minutes, and it is stirred for 0.5 hour at a bathtemperature of 90° C. This solution is added to a solution of 3.16 g oftetrakistriphenylphosphine palladium (O) and 24 g of2-benzyloxy-6-bromo-5-(4-methoxyphenyl)-8,9-dihydro-7H-benzocycloheptenein 144 ml of tetrahydrofuran, and it is stirred for another 3 hours at abath temperature of 90° C. Then, it is added to 170 ml of a 1Mhydrochloric acid, extracted three times with ethyl acetate, dried onsodium sulfate, concentrated by evaporation in a vacuum and absorptivelyprecipitated with diethyl ether. 22.53 g of2-benzyloxy-5-(4-methoxyphenyl)-6-phenyl-8,9-dihydro-7H-benzocyclohepteneis obtained as crystals with a melting point of 163-164° C.

e) 5-(4-Methoxyphenyl)-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol

A solution of 21.16 g of2-benzyloxy-5-(4-methoxyphenyl)-6-phenyl-8,9-dihydro-7H-benzocycloheptenein 900 ml of dichloromethane is stirred at 0° C. with 19 ml ofN,N-dimethylaniline for 5 minutes, mixed in portions with 26.1 g ofaluminum chloride and stirred for another 3 hours at 0° C. Then, it ismixed with 1 M hydrochloric acid, added to water, extracted three timeswith dichloromethane, washed neutral, dried on sodium sulfate,concentrated by evaporation in a vacuum and absorptively precipitatedwith hexane/diethyl ether. 17.4 g of5-(4-methoxyphenyl)-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol isobtained as crystals with a melting point of 232-233° C.

f)2-[5-(4-Methoxyphenyl)-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy]-tetrahydropyran

A suspension of 15.8 g of5-(4-methoxyphenyl)-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol in 150ml of toluene is stirred with 15 ml of dihydropyran and 60 mg ofparatoluenesulfonic acid-monohydrate for 18 hours at room temperature.Then, it is diluted with ethyl acetate, washed with sodium bicarbonateand common salt solution, dried on sodium sulfate and concentrated byevaporation in a vacuum. 19.7 g of2-[5-(4-methoxyphenyl)-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy]-tetrahydropyranis obtained as crystals with a melting point of 131-133° C.

g)4-[6-Phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenol

A solution of 19.7 g of2-[5-(4-methoxyphenyl)-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy]-tetrahydropyranin 500 ml of dimethylformamide is stirred with 9.73 g of sodiummethylthiolate for 6.5 hours at a bath temperature of 140° C. Then, itis added to water, extracted three times with ethyl acetate, washedneutral, dried on sodium sulfate, concentrated by evaporation in avacuum and chromatographed on silica gel with hexane/ethyl acetate. 17.2g of4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenolis obtained as crystals with a melting point of 183-185° C.

h)2-{5-[4-(5-Chloropentyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydropyran

A solution of 6.0 g of4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydroxy-7H-benzocyclohepten-5-yl]-phenolin 77 ml of acetonitrile is stirred with 2.55 g of potassium carbonateand 2.27 ml of 1-bromo-5-chloropentane for 9 hours at 90° C. Then, it isadded to water, extracted three times with ethyl acetate, washedneutral, dried on sodium sulfate, concentrated by evaporation in avacuum and chromatographed on silica gel with hexane/ethyl acetate. 6.9g of2-{5-[4-(5-chloropentyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydro-pyranis obtained as crystals with a melting point of 99-101° C.

i)5-[4-(5-chloropentyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol

A solution of 6.7 g of2-{5-[4-(5-chloropentyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydropyranin 130 ml of methanol and 13 ml of water is stirred with 5.7 g of oxalicacid for 1 hour at a bath temperature of 100° C. Then, it isconcentrated by evaporation in a vacuum to 50 ml, added to water,extracted three times with ethyl acetate, washed neutral, dried onsodium sulfate, evaporated to the dry state in a vacuum andrecrystallized from ethyl acetate. 5.48 g of5-[4-(5-chloropentyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olis obtained as crystals with a melting point of 200-202° C.

j)5-[4-(5-Iodopentyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol

A solution of 5.28 g of5-[4-(5-chloropentyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ylin 185 ml of ethylmethylketone is stirred with 6.9 g of sodium iodidefor 24 hours at a bath temperature of 100° C. Then, it is added towater, extracted three times with ethyl acetate, washed neutral, driedon sodium sulfate, concentrated by evaporation in a vacuum andcrystallized from acetone/hexane. 5.86 g of5-[4-(5-iodopentyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olis obtained as crystals with a melting point of 192-193° C.

k)5-{4-[5-(4,4,5,5,5-Pentafluoro-pentylthio)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol

A solution of 1.7 g of 4,4,5,5,5-pentafluoropentylthioacetate in 9 ml ofmethanol is stirred with 1.36 ml of a 30% methanolic sodium methylsolution at room temperature for 0.5 hour. This solution is added indrops to a suspension of 3 g of5-[4-(5-iodopentyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olin 35 ml of methanol and 35 ml of diethyl ether, and it is stirred for 4hours at room temperature. Then, it is concentrated by evaporation in avacuum to 15 ml, added to water, extracted three times with ethylacetate, washed neutral, dried on sodium sulfate and evaporated to thedry state in a vacuum. 3.38 g of5-{4-[5-(4,4,5,5,5-pentafluoro-pentylthio)-pentyloxy]-phenyl}6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olis obtained as crystals with a melting point of 167-168° C.

Example 9=ZU 186 6195-{4-[5-(4,4,5,5,5-Pentafluoro-pentanesulfinyl)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol

Analogously to what is described in Example 2, 2.38 g of5-{4-[5-(4,4,5,5,5-pentafluoro-pentylthio)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olis oxidized, and 2.2 g of5-{4-[5-(4,4,5,5,5-pentafluoro-pentanesulfinyl)-pentyloxy]-phenyl)-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olis obtained as crystals with a melting point of 138-140° C.

Example 105-[4-(2-{Methyl-[3-(4,4,5,5,5-pentafluoro-pentane-sulfinyl)-propyl]-amino}-ethoxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol

Analogously to what is described in Example 2, 0.8 g of5-[4-(2-{methyl-[3-(4,4,5,5,5-pentafluoro-pentylthio)-propyl]amino}-ethoxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olis oxidized, and 405 mg of5-[4-(2-{methyl-[3-(4,4,5,5,5-pentafluoro-pentanesulfinyl)-propyl]-amino}-ethoxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olis obtained as crystals with a melting point of 63-65° C.

Example 115-[4-(2-Methyl-[3-(4,4,5,5,5-pentafluoro-pentylthio)-propyl]-amino}-ethoxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ola)2-{5-[4-(2-Chloroethyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydropyran

A solution of 6.0 g of4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenolin 77 ml of acetonitrile is stirred with 2.55 g of potassium carbonateand 2.27 ml of 1-bromo-5-chloropentane for 9 hours at 90° C. Then, it isadded to water, extracted three times with ethyl acetate, washedneutral, dried on sodium sulfate, concentrated by evaporation in avacuum and chromatographed on silica gel with hexane/ethyl acetate. 6.7g of2-{5-[4-(2-chloroethyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy)-tetrahydropyranis obtained as crystals with a melting point of 153-155° C.

b)5-[4-(2-Chloroethyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol

A solution of 6.6 g of2-{5-[4-(2-chloroethyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydropyranin 130 ml of methanol and 13 ml of water is stirred with 5.7 g of oxalicacid for 1 hour at a bath temperature of 100° C. Then, it isconcentrated by evaporation in a vacuum to 50 ml, added to water,extracted three times with ethyl acetate, washed neutral, dried onsodium sulfate, evaporated to the dry state in a vacuum andrecrystallized from ethyl acetate. 5.0 g of5-[4-(2-chloroethyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olis obtained as crystals with a melting point of 238-240° C.

c)5-[4-(2-Iodoethyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol

A solution of 5.0 g of5-[4-(2-chloroethyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olin 190 ml of ethylmethylketone is stirred with 7.24 g of sodium iodidefor 28 hours at a bath temperature of 100° C. Then, it is added towater, extracted three times with ethyl acetate, washed neutral, driedon sodium sulfate, concentrated by evaporation in a vacuum andcrystallized from acetone/hexane. 5.9 g of5-[4-(2-iodoethyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olis obtained as crystals with a melting point of 229-231° C.

d)5-{4-[2-(Methylamino)-ethoxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol

A solution of 4.5 g of5-[4-(2-iodoethyloxy)-phenyl]6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olin 100 ml of 2-methoxyethanol is stirred with 7.2 ml of a 40% aqueousmethylamine solution for 2 hours at a bath temperature of 100° C. Then,it is added to saturated common salt solution, extracted three timeswith ethyl acetate, washed neutral, dried on sodium sulfate,concentrated by evaporation in a vacuum and absorptively precipitatedfrom ethyl acetate. 2.7 g of5-{4-[2-(methylamino)-ethoxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olis obtained as crystals with a melting point of 184-187° C.

e)5-[4-(2-{Methyl-[3-(4,4,5,5,5-pentafluoro-pentylthio)-propyl]-amino}-ethoxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol

A solution of 1.7 g of5-{4-[2-(methylamino)-ethoxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olin 34 ml of 2-methoxyethanol is mixed drop by drop with 3.4 ml of1-iodo-3-(4,4,5,5,5-pentafluoropentylthio)-propane, and it is stirredfor 1 hour at a bath temperature of 140° C. Then, it is added to water,extracted three times with ethyl acetate, washed neutral, dried onsodium sulfate, concentrated by evaporation in a vacuum and crystallizedfrom acetone/hexane. 1.1 g of5-[4-(2-{methyl-[3-(4,4,5,5,5-pentafluoro-pentylthio)-propyl]amino}-ethoxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olis obtained as crystals with a melting point of 40-42° C.

Example 12N-Butyl-N-methyl-2-{5-[4-(2-hydroxy-6-phenyl-8,9-dihydroxy-7H-benzocyclohepten-5-yl)-phenoxy]-pentylthio}-acetamidea)2-{5-[4-(5-Iodopentyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy3-tetrahydropyran

A solution of 1.25 g of2-{5-[4-(5-chloropentyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydropyranin 40 ml of ethylmethylketone is stirred with 1.38 g of sodium iodidefor 9 hours at a bath temperature of 100° C. Then, it is added to water,extracted three times with ethyl acetate, washed neutral, dried onsodium sulfate, concentrated by evaporation in a vacuum andchromatographed on silica gel with hexane/ethyl acetate. 0.7 g of2-{5-[4-(5-iodopentyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydropyranis obtained as crystals with a melting point of 109-111° C.

b)S-{5-[4-(6-Phenyl-2-tetrahydropyranyloxy-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentyl}-thioacetate

A solution of 0.7 g of2-{5-[4-(5-iodopentyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydropyranin 15 ml of acetone is stirred with 392 mg of potassium thioacetate for2 hours at room temperature. Then, it is added to water, extracted threetimes with ethyl acetate, washed neutral, dried on sodium sulfate,concentrated by evaporation in a vacuum and chromatographed on silicagel with hexane/ethyl acetate. 550 mg ofS-{5-[4-(6-phenyl-2-tetrahydropyranyloxy-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentyl}-thioacetateis obtained as crystals with a melting point of 84-86° C.

c)N-Butyl-N-methyl-2-{5-[4-(6-phenyl-2-tetrahydropyranyloxy-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentylthio}-acetamide

A solution of 0.5 g ofS-{5-[4-(6-phenyl-2-tetrahydropyranoyloxy-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentyl}-thioacetatein 8 ml of methanol and 5 ml of tetrahydrofuran is stirred with 0.2 mlof a 30% methanolic sodium methylate solution of 0.5 hour at roomtemperature, and after 0.25 ml of 2-bromo-N-butyl-N-methyl-acetamide isadded, it is stirred for another hour. Then, it is added to water,extracted three times with ethyl acetate, washed neutral, dried onsodium sulfate, concentrated by evaporation in a vacuum andchromatographed on silica gel with hexane/ethyl acetate. 450 mg ofN-butyl-N-methyl-2-{5-[4-(6-phenyl-2-tetrahydropyranyloxy-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentylthio}-acetamideis obtained as an oil.

d)N-Butyl-N-methyl-2-{5-[4-(2-hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentylthio}-acetamide

A solution of 400 g ofN-butyl-N-methyl-2-{5-[4-(6-phenyl-2-tetrahydropyranyloxy-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentylthio}-acetamidein 11 ml of methanol nd 1.1 ml of water is stirred with 0.4 g of oxalicacid for 1 hour at a bath temperature of 100° C. Then, it is added towater, extracted three times with ethyl acetate, washed neutral, driedon sodium sulfate, evaporated to the dry state in a vacuum andrecrystallized from pentane. 360 mg ofN-butyl-N-methyl-2-[5-[4-(2-hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentylthio}-acetamideis obtained as crystals with a melting point of 112-114° C.

Example 135-{4-[5-(4,4,5,5,5-Pentafluoro-pentanesulfonyl)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ola)2-{5-[4-(5-(4,4,5,5,5-Pentafluoro-pentanesulfonyl)-pentyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydropyran

A suspension of 0.5 g of4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenol(Example 8 g) in 7 ml of tetrahydrofuran is stirred with 212.5 mg ofpotassium carbonate and 620 mg of1-iodo-5-(4,4,5,5,5-pentafluoropentanesulfonyl)-pentane for 11 hours ata bath temperature of 100° C. Then, it is added to water, extractedthree times with ethyl acetate, washed neutral, dried on sodium sulfate,concentrated by evaporation in a vacuum and chromatographed on silicagel with hexane/ethyl acetate. 770 mg of2-{5-[4-(5-(4,4,5,5,5-pentafluoro-pentanesulfonyl)-pentyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydropyranis obtained as crystals with a melting point of 107-110° C.

b)5-{4-[5-(4,4,5,5,5-Pentafluoro-pentanesulfonyl)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol

A solution of 0.7 g of2-{5-[4-(5-(4,4,5,5,5-pentafluoro-pentanesulfonyl)-pentyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy]-tetrahydropyranin 16 ml of methanol and 1.6 ml of water is stirred with 0.7 g of oxalicacid for 1 hour at a bath temperature of 100° C. Then, it isconcentrated by evaporation in a vacuum to 50 ml k, added to water,extracted three times with ethyl acetate, washed neutral, dried onsodium sulfate, evaporated to the dry state in a vacuum andrecrystallized from ethyl acetate. 0.46 g of5-{4-[5-(4,4,5,5,5-pentafluoro-pentanesulfonyl)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olis obtained as crystals with a melting point of 176-178° C.

Example 14N-Butyl-N-methyl-2-{5-[4-(2-hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentanesulfinyl}-acetamide

Analogously to what is described in Example 2, 210 mg ofN-butyl-N-methyl-2-{5-[4-(2-hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentylthio)-acetamide(Example 12) is oxidized, and 132 mg ofN-butyl-N-methyl-2-{5-[4-(2-hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-pentanesulfinyl}-acetamideis obtained as crystals with a melting point of 87-89° C.

Example 15N-Butyl-2-[2-({2-[4-(2-hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-ethyl}-methyl-amino)-ethanesulfinyl]-N-methyl-acetamidea)2-{5-[4-(2-Iodoethyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy]-tetrahydropyran

Analogously to what is described in Example 11c, a solution of 1.7 g of2-{5-[4-(2-chloroethyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy}{-tetrahydropyran(Example 11a) is iodized, and 2 g of2-{5-[4-(2-iodoethyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydropyranis obtained as crystals with a melting point of 165-166° C.

b)2-{5-{4-[2-(Methylamino)-ethoxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydropyran

A solution of 2 g of2-{5-[4-(2-iodoethyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydropyranin 45 m of 2-methoxyethanol is stirred with 3.2 ml of a 40% aqueousmethylamine solution of 2 hours at a bath temperature of 100° C. Then,it is added to saturated sodium bicarbonate solution, extracted threetimes with ethyl acetate, washed neutral, dried on sodium sulfate andconcentrated by evaporation in a vacuum. 1.65 g of2-{5-{4-[2-(methylamino)-ethoxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydropyranis obtained as crystals with a melting point of 133-137° C.

c)N-Butyl-2-[2-({2-[4-(6-phenyl-2-tetrahydropyranyloxy-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-ethyl}-methyl-amino)-ethanesulfinyl]-N-methyl-acetamide

A solution of 825 mg of2-{5-{4-[2-(methylamino)-ethoxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydropyranin 20 ml of 2-methoxyethanol is stirred with 583 mg ofN-butyl-2-iodoethanesulfinyl-N-methyl-acetamide for 3.5 hours at a bathtemperature of 120° C. Then, it is added to common salt solution,extracted three times with ethyl acetate, washed neutral, dried onsodium sulfate, concentrated by evaporation in a vacuum andchromatographed on silica gel with dichloromethane/methanol. 0.72 g ofN-butyl-2-[2-({2-[4-(6-phenyl-2-tetrahydropyranyloxy-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-ethyl}-methyl-amino)-ethanesulfinyl]-N-methyl-acetamideis obtained as foam.

d)N-Butyl-2-{2-({2-[4-(2-hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-ethyl}-methyl-amino)-ethanesulfinyl]-N-methyl-acetamide

Analogously to what is described in 11b, 245 mg ofN-butyl-2-[2-({2-[4-(2-hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-ethyl}-methyl-amino)-ethanesulfinyl]-N-methyl-acetamideis obtained as crystals with a melting point of 72-74° C. from 720 mg ofN-butyl-2-[2-({2-[4-(6-phenyl-2-tetrahydropyranyloxy-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-ethyl}-methyl-amino)-ethanesulfinyl]-N-methyl-acetamide.

Example 16N-Butyl-2-[2-({2-[4-(2-hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-ethyl}-methyl-amino)-ethanesulfonyl]-N-methyl-acetamidea)N-Butyl-2-[2-({2-[4-(6-phenyl-2-tetrahydropyranyloxy-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-ethyl}-methyl-amino)-ethanesulfonyl]-N-methyl-acetamide

A solution of 825 mg of2-{5-{4-[2-(methylamino)-ethoxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydropyranin 20 ml of 2-methoxyethanol is stirred with 607 mg ofN-butyl-2-iodoethanesulfonyl-N-methyl-acetamide for 3.5 hours at a bathtemperature of 120° C. Then, it is added to common salt solution,extracted three times with ethyl acetate, washed neutral, dried onsodium sulfate, concentrated by evaporation in a vacuum andchromatographed on silica gel with dichloromethane/methanol. 324 mg ofN-butyl-2[2-({2-[4-(6-phenyl-2-tetrahydropyranyloxy-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-ethyl}-methyl-amino)-ethanesulfonyl]-N-methyl-acetamideis obtained as a foam.

b)N-Butyl-2-[2-({2-[4-(2-hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-ethyl}-methyl-\amino)-ethanesulfonyl]-N-methyl-acetamide

Analogously to what is described in Example 11b, 231 mg ofN-butyl-2-[2-({2-[4-(2-hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-ethyl}-methyl-amino)-ethanesulfonyl]-N-methyl-acetamideis obtained from 300 mg ofN-butyl-2-[2-({2-[4-(6-phenyl-2-tetrahydropyranyloxy-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-ethyl}-methyl-amino)-ethanesulfonyl]-N-methyl-acetamideas crystals with a melting point of 57-60° C.

Example 176-(4-Hydroxy-phenyl)-5-{4-[5-(4,4,5,5,5-pentafluoro-pentanesulfonyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ola)2-Benzyloxy-6-(4-tert-butyldimethylsilyloxyphenyl)-5-(4-methoxyphenyl)-8,9-dihydro-7H-benzocycloheptene

A solution of 10 g of2-benzyloxy-6-bromo-5-(4-methoxyphenyl)-8,9-dihydro-7H-benzocycloheptene(Example 8c) in 114 ml of toluene and 57 ml of ethanol is stirred with5.81 g of [4-(tert-butyldimethylsilyloxy)-phenyl]-boric acid, 23 ml ofaqueous 2 M-sodium carbonate solution and 246 mg oftetrakistriphenylphosphine palladium(O) for 1 hour at a bath temperatureof +90° C. Then, it is diluted with ethyl acetate, washed twice withwater and common salt solution, dried on sodium sulfate and concentratedby evaporation in a vacuum. 13 g of2-benzyloxy-6-(4-tert-butyldimethylsilyloxyphenyl)-5-(4-methoxyphenyl)-8,9-dihydro-7H-benzocyclohepteneis obtained.

b)4-[2-Benzyloxy-5-(4-methoxyphenyl)-8,9-dihydro-7H-benzocyclohepten-6-yl]-phenol

A suspension of 13 g of2-benzyloxy-6-(4-tert-butyldimethylsilyloxyphenyl)-5-(4-methoxyphenyl)-8,9-dihydro-7H-benzocycloheptenein 235 ml of methanol is stirred with 7.25 ml of concentratedhydrochloric acid for 7.5 hours at a bath temperature of 50° C. Then, itis neutralized wtih sodium bicarbonate, concentrated by evaporation in avacuum, added to water, extracted three times with ethyl acetate, washedwith common salt solution, dried on sodium sulfate, concentrated byevaporation in a vacuum and recrystallized from methanol. 10.3 g of4-[2-benzyloxy-5-(4-methoxyphenyl)-8,9-dihydro-7H-benzocyclohepten-6-yl]-phenolis obtained as crystals with a melting point of 173-175° C.

c)5-(4-Methoxyphenyl)-6-(4-hydroxyphenyl)-8,9-dihydro-7H-benzocyclohepten-2-ol

A solution of 10.3 g of4-[2-benzyloxy-5-(4-methoxyphenyl)-8,9-dihydro-7H-benzocyclohepten-6-yl]-phenolin 350 ml of dichloromethane is stirred at 0° C. with 8.76 ml ofN,N-dimethylaniline for 5 minutes and stirred with 12.2 g of aluminumchloride for 4.5 hours at 0° C. Then, it is mixed at 0° C. with 2 Mhydrochloric acid, added to water, extracted three times withdichloromethane, washed neutral, dried on sodium sulfate, concentratedby evaporation in a vacuum and absorptively precipitated with diethylether and a little dichloromethane. 7.8 g of5-(4-methoxyphenyl)-6-(4-hydroxyphenyl)-8,9-dihydro-7H-benzocyclohepten-2-olis obtained as crystals with a melting point of 250-252° C.

d)2-[5-(4-Methoxyphenyl)-6-(4-tetrahydropyranyloxyphenyl)-8,9-dihydro-7H-benzocyclohepten-2-yloxy]-tetrahydropyran

A solution of 7.8 g of5-(4-methoxyphenyl)-6-(4-hydroxyphenyl)-8,9-dihydro-7H-benzocyclohepten-2-olin 80 ml of toluene and 40 ml of tetrahydrofuran is stirred with 17.4 mlof dihydropyran and 71.4 mg of paratoluenesulfonic acid for 20 hours atroom temperature. Then, it is diluted with ethyl acetate, washed withsodium bicarbonate and common salt solution, dried on sodium sulfate,concentrated by evaporation in a vacuum and absorptively precipitatedwith diethyl ether and a little ethyl acetate. 8.1 g of2-[5-(4-methoxyphenyl)-6-(4-tetrahydropyranyloxyphenyl)-8,9-dihydro-7H-benzocyclohepten-2-yloxy]-tetrahydropyranis obtained as crystals with a melting point of 160-161° C.

e)4-[2-Tetrahydropyranyloxy-6-(4-tetrahydropyranyloxyphenyl)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenol

A solution of 8.0 g of4-[2-tetrahydropyranyloxy-6-(4-tetrahydropyranyloxyphenyl)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenolin 160 ml of dimethylformamide is stirred with 3.2 g of sodiummethanethiolate for 7 hours at 140° C. Then, it is added to water,extracted three times with ethyl acetate, washed neutral, dried onsodium sulfate, concentrated by evaporation in a vacuum and absorptivelyprecipitated with diethyl ether. 7.4 g of4-[2-tetrahydropyranyloxy-6-(4-tetrahydropyranyloxyphenyl)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenolis obtained as crystals with a melting point of 182-183° C.

f)2-{5-[4-(5-(4,4,5,5,5-Pentafluoro-pentanesulfonyl)-pentyloxy]-phenyl]-6-(4-tetrahydropyranyloxyphenyl)-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydropyran

A suspension of 1 g of-[2-tetrahydropyranyloxy-6-(4-tetrahydropyranyloxyphenyl)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenolin 14 ml of acetonitrile is refluxed with 342 mg of potassium carbonateand 1 g of 1-iodo-5-(4,4,5,5,5-pentafluoropentanesulfonyl)-pentane for21 hours at a bath temperature of 100° C. Then, it is concentrated byevaporation in a vacuum, added to water, extracted three times withethyl acetate, washed neutral, dried on sodium sulfate, concentrated byevaporation in a vacuum and recrystallized from diethyl ether. 1.6 g of2-{5-[4-(5-(4,4,5,5,5-pentafluoro-pentanesulfonyl)-pentyloxy)-phenyl]-6-(4-tetrahydropyranyloxyphenyl)-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydropyranis obtained as crystals with a melting point of 108-110° C.

g)6-(4-Hydroxy-phenyl)-5-{4-[5-(4,4,5,5,5-pentafluoro-pentanesulfonyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol

A suspension of 1.5 g of6-(4-hydroxy-phenyl)-5-{4-[5-(4,4,5,5,5-pentafluoro-pentanesulfonyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-olin 34 ml of methanol as well as 3.4 ml of water is stirred with 1.5 g ofoxalic acid for 1 hour at 100° C. Then, it is added to water, extractedthree times with ethyl acetate, washed neutral, dried on sodium sulfate,concentrated by evaporation in a vacuum and chromatographed withhexane/diethyl ether. 924 mg of6-(4-hydroxy-phenyl)-5-{4-[5-(4,4,5,5,5-pentafluoro-pentanesulfonyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-olis obtained as crystals with a melting point of 168-170° C.

Example 18N-Butyl-2-{6-[4-(2-hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-hexanesulfinyl}-N-methyl-acetamide

Analogously to what is described in Example 2, 0.4 g ofN-butyl-2-{6-[4-(2-hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-hexylthio}-N-methyl-acetamide(Example 19) is oxidized, and 394 mg ofN-butyl-2-{6-[4-(2-hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-hexanesulfinyl}-N-methyl-acetamideis obtained as crystals with a melting point of 72-73° C.

Example 19N-Butyl-2-{6-[4-(2-hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-hexylthio}-N-methyl-acetamidea)2-{5-[4-(6-Chlorohexyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydropyran

Analogously to what is described in Example 8h, 1.2 g of4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenol(Example 8g) is alkylated with 0.52 ml of 1-bromo-6-chlorohexane, and1.1 g of2-{5-[4-(6-chlorohexyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydropyranis obtained as crystals with a melting point of 84-86° C.

b)2-{5-[4-(6-Iodohexyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydropyran

Analogously to what is described in Example 12a, 1 g of2-{5-[4-(6-chlorohexyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydropyranis substituted with 1.07 g of sodium iodide, and 1.1 g of2-{5-[4-(6-iodohexyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydropyranis obtained as crystals with a melting point of 108-110° C.

c)S-{6-[4-(6-Phenyl-2-tetrahydropyranyloxy-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-hexyl}-thioacetate

Analogously to what is described in Example 12b, 1 g of2-{5-[4-(6-iodohexyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydropyranis thioacetylated with 549 mg of potassium thioacetate, and 916 mg ofS-{6-[4-(6-phenyl-2-tetrahydropyranyloxy-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-hexyl}-thioacetateis obtained as crystals with a melting point of 98-100° C.

d)N-Butyl-N-methyl-2-{6-[4-(6-phenyl-2-tetrahydropyranyloxy-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-hexylthio}-acetamide

Analogously to what is described in Example 12c, 0.8 g ofS-{6-[4-(6-phenyl-2-tetrahydropyranyloxy-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-hexyl}-thioacetateis reacted with 0.31 g of 2-bromo-N-butyl-N-methyl-acetamide to 632 mgofN-butyl-N-methyl-2-[6-[4-(6-phenyl-2-tetrahydropyranyloxy-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-hexylthio}-acetamide.

e)N-Butyl-2-{6-[4-(2-hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-hexylthio}-N-methyl-acetamide

Analogously to what is described in Example 12d, 0.6 g ofN-butyl-N-methyl-2-{6-[4-(6-phenyl-2-tetrahydropyranyloxy-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-hexylthio}-acetamideis reacted with 0.6 g of oxalic acid to 520 mg ofN-butyl-2-{6-[4-(2-hydroxy-6-phenyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy]-hexylthio}-N-methyl-acetamide as crystals with a melting point of 103-105° C.

Example 206-(4-Hydroxy-phenyl)-5-{4-[5-(4,4,5,5,5-pentafluoropentylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ola)2-{5-[4-(5-Chloropentyloxy)-phenyl]-6-(4-tetrahydropyranyloxyphenyl)-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydropyran

Analogously to what is described in Example 8h, 2 g of4-[2-tetrahydropyranyloxy-6-(4-tetrahydropyranyloxyphenyl)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenol(Example 17e) is alkylated with 0.61 ml of 1-bromo-5-chloropentane, and2.4 g of2-{5-[4-(5-chloropentyloxy)-phenyl]-6-(4-tetrahydropyranyloxyphenyl)-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydropyranis obtained as crystals with a melting point of 110-112° C.

b)2-{5-[4-(5-Iodopentyloxy)-phenyl]-6-(4-tetrahydropyranyloxyphenyl)-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydropyran

Analogously to what is described in Example 12a, 2.3 g of2-{5-[4-(5-chloropentyloxy)-phenyl[-6-(4-tetrahydropyranyloxyphenyl)-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydropyranis substituted with 2.13 g of sodium iodide, and 2.6 g of2-{5-[4-(5-iodopentyloxy)-phenyl]-6-(4-tetrahydropyranyloxyphenyl)-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydropyranis obtained.

c)6-(4-Hydroxy-phenyl)-5-[4-(5-iodopentyloxy)-phenyl]-8,9-dihydro-7H-benzocyclohepten-2-ol

Analogously to what is described in Example 12d, 2.6 g of2-{5-[4-(5-iodopentyloxy)-phenyl]-6-(4-tetrahydropyranyloxyphenyl)-8,9-dihydro-7H-benzocyclohepten-2-yloxy)-tetrahydropyranis reacted with 2.6 g of oxalic acid, and 2 g of6-(4-hydroxy-phenyl)-5-[4-(5-iodopentyloxy)-phenyl]-8,9-dihydro-7H-benzocyclohepten-2-olis obtained as crystals with a melting point of 202-204° C.

d)6-(4-Hydroxy-phenyl)-5-{4-[5-(4,4,5,5,5-pentafluoropentylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol

Analogously to what is described in Example 8k, 1.9 g of6-(4-hydroxy-phenyl)-5-[4-(5-iodopentyloxy)-phenyl]-8,9-dihydro-7H-benzocyclohepten-2-olis reacted with 1.7 g of 4,4,5,5,5-pentafluoropentylthioacetate. 1.4 gof6-(4-hydroxy-phenyl)-5-{4-[5-(4,4,5,5,5-pentafluoropentylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-olis obtained as crystals with a melting point of 157-158° C.

Example 216-(4-Hydroxy-phenyl)-5-{4-[5-(4,4,5,5,5-pentafluoropentane-sulfinyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol

Analogously to what is described in Example 2, 1.3 g of6-(4-hydroxy-phenyl)-5-{4-[5-(4,4,5,5,5-pentafluoropentylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-olis oxidized, and 2.2 g of6-(4-hydroxy-phenyl)-5-{4-[5-(4,4,5,5,5-pentafluoropentane-sulfinyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-olis obtained a crystals with a melting point of 165-168° C.

Example 225-{4-[4-(4,4,5,5,5-Pentafluoro-pentylthio)-butyloxy)-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ola)2-{5-[4-(4-Chloro-butyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydropyran

4.8 g of4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenol(Example: 8g) is introduced into 50 ml of acetonitrile, mixed at roomtemperature with 2.04 g of potassium carbonate and 1.61 ml of1-bromo-4-chlorobutane and stirred for 8 hours at 90° C. Base on anincomplete reaction, 20% of the amount of potassium carbonate and1-bromo-4-chlorobutane that are used at the beginning are added againand heated for another 6 hours at 90° C. For working-up, the preparationis concentrated by evaporation in a vacuum, mixed with water, extractedthree times with ethyl acetate, washed with saturated sodium chloridesolution, dried on magnesium sulfate and concentrated by evaporation ina vacuum. The residue is purified on silica gel with a hexane-ethylacetate gradient. 5.18 g of2-[5-[4-(4-chloro-butyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydropyranis obtained.

b)5-[4-(4-Chloro-butyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol

5.15 g of2-{5-[4-(4-chloro-butyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydropyranis suspended in 100 ml of methanol and 10 ml of water, mixed with 4.47 gof oxalic acid and stirred for 75 minutes at 100° C. The solvent isdrawn off in half in a vacuum, the preparation is added to water,extracted three times with ethyl acetate, washed with saturated sodiumchloride solution, dried on magnesium sulfate and concentrated byevaporation in a vacuum. Preparative column chromatography on silica gelwith a hexane-ethyl acetate gradient yields 5.01 g of5-[4-(4-chloro-butyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol.

c)5-[4-(4-Iodo-butyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol

2.0 g of5-(4-(4-chloro-butyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olis introduced into 72 ml of ethylmethylketone, mixed with 2.70 g ofsodium iodide and refluxed for 12 hours at 100° C. The cooled reactionmixture is concentrated by evaporation in a vacuum, mixed with water andextracted three times with ethyl acetate. The organic phase is thenwashed with sodium thiosulfate solution and saturated sodium chloridesolution. Drying on magnesium sulfate and concentration by evaporationin a vacuum yields 2.14 g of5-[4-(4-iodo-butyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol,which is used without further purification in the next stage.

d)5-{4-[4-(4,4,5,5,5-Pentafluoro-pentylthio)-butyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol

A solution of 1.22 g of 4,4,5,5,5-pentafluoropentylthioacetate in 6 mlof methanol is stirred wtih 0.98 ml of a 30% methanolic sodium methylatesolution at room temperature for 0.5 hour. This solution is added indrops to a suspension of 2.1 g of5-[4-(4-iodo-butyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olin 25 ml of methanol and 25 ml of diethyl ether, and it is stirred for 4hours at room temperature. Then, the reaction mixture is concentrated byevaporation in a vacuum, added to water, extracted three times withethyl acetate, washed neutral, dried on magnesium sulfate andconcentrated by evaporation in a vacuum. Column chromatographicseparation on silica gel with a hexane/ethyl acetate gradient yields1.84 g of5-{4-[4-(4,4,5,5,5-pentafluoro-pentylthio)-butyloxy]-phenyl}-6-phenyl-8:,9-dihydro-7H-benzocyclohepten-2-olwith-a melting point of: 167° C.

Example 236-Phenyl-5-{4-[4-(pyridin-2-ylmethylthio)-butyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol

12.3 goof a 10% ethanolic 2-mercaptomethylpyridine solution is mixed atroom temperature drop by drop with 1.67 ml of a 30% methanolic sodiummethylate solution, and it is stirred for 15 more minutes. Then, thesolution is added in drops to a suspension of 1.70 g of5-[4-(4-iodo-butyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol(Example: 22c) in 16 ml of methanol, and it is refluxed for 2 hours at abath temperature of 80° C. Solvent is removed from the cooled reactionmixture, the residue is mixed with semisaturated sodium chloridesolution, extracted three times with ethyl acetate, washed withsaturated sodium chloride solution, dried on magnesium sulfate andconcentrated by evaporation in a vacuum. Column chromatographicpurification on silica gel with a hexane-ethyl acetate gradient yields1.37 g of6-phenyl-5-{4-[4-(pyridin-2-ylmethylthio)-butyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-olwith a melting point of: 155° C.

Example 246-Phenyl-5-{4-[5-(pyridin-2-ylmethylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol

21.4 g of a 10% ethanolic 2-mercaptomethylpyridine solution is mixed atroom temperature drop by drop with 2.91 ml of a 30% methanolic sodiummethylate solution, and it is stirred for 15 more minutes. Then, thesolution is added in drops to a suspension of 2.52 g of5-[4-(5-chloropentyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol(Example: 8i) and 1.03 g of sodium iodide in 29 ml of methanol, and itis refluxed for 2 hours at a bath temperature of 80° C. For working-up,the reaction mixture is allowed to reach room temperature, and thesolvent is removed in a vacuum. The residue is mixed with semisaturatedsodium chloride solution, extracted three times with ethyl acetate,washed with saturated sodium chloride solution, dried on mag sulfate andconcentrated by evaporation in a vacuum. Recrystallization from ethylacetate results in 2.15 g of6-phenyl-5-{4-[5-(pyridin-2-ylmethylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-olwith a melting point of: 159° C.

Example 256-Phenyl-5-{4-[6-(pyridin-2-ylmethylthio)-hexyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol

16.8 g of a 10% ethanolic 2-mercaptomethylpyridine solution is mixed atroom temperature drop by drop with 2.30 ml of a 30% methanolic sodiummethylate solution, and it is stirred for 15 more minutes. Then, thesolution is added in drops to a suspension of 2.05 g of5-[4-(6-chlorohexyloxy)-phenyl)-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol(Example: 28a) and 812 mg of sodium iodide in 22 ml of methanol,and itis refluxed for 2 hours at a bath temperature of 80° C. For working-up,the reaction mixture is allowed to reach room temperature, and thesolvent is removed in a vacuum. The residue is mixed with semisaturatedsodium chloride solution, extracted three times with ethyl acetate,washed with saturated common salt solution, dried on magnesium sulfateand concentrated by evaporation in a vacuum. Recrystallization fromethyl acetate results in 1.63 g of6-phenyl-5-{4-[6-(pyridin-2-ylmethylthio)-hexyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-olwith a melting point of: 127° C.

Example 265-{4-[4-(4,4,5,5,5-Pentafluoro-pentanesulfinyl)-butyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol

1.41 g of5-{4-[4-(4,4,5,5,5-pentafluoro-pentylthio)-butyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol(Example: 22d) is suspended in 40 ml of methanol and 2.32 ml of water,mixed with 550 mg of sodium periodate and stirred for 12 hours at roomtemperature. Then, the methanol is drawn off in a vacuum, the residue isadded to water, extracted three times with ethyl acetate, washed withsaturated sodium chloride solution, dried on magnesium sulfate andconcentrated by evaporation in a vacuum. Trituration of the crudeproduct with hexane results in 1.39 g of5-{4-(4-(4,4,5,5,5-pentafluoro-pentanesulfinyl)-butyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olwith a melting point of: 155° C.

Example 276-Phenyl-5-{4-[4-(pyridin-2-ylmethanesulfinyl)-butyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol

990 mg of6-phenyl-5-{4-[4-(pyridin-2-ylmethylthio)-butyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol(Example: 23) is suspended in 3.2 ml of methanol and 1.85 ml of water,mixed with 440 mg of sodium periodate and stirred overnight at roomtemperature. On the following day, the preparation is heated for 75minutes to 50° C. For working-up, the solvent is removed in a vacuum,the residue is mixed with water, extracted three times with ethylacetate, washed with saturated sodium chloride solution, dried onmagnesium sulfate and concentrated by evaporation in a vacuum.Purification of the crude product on silica gel with a methylenechloride-methanol gradient yields 612 mg of6-phenyl-5-{4-[4-(pyridin-2-ylmethanesulfinyl)-butyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-olwith a melting point of: 162° C.

Example 285-{4-[6-(4,4,5,5,5-Pentafluoro-pentylthio)-hexyloxy}-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ola)5-[4-(6-Chloro-hexyloxy)-phenyl)-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol

5.42 g of2-{5-[4-(6-chloro-hexyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydropyran(Example: 19a) is dissolved in 100 ml of tetrahydrofuran and 10 ml ofwater, mixed with 4.674 g of oxalic acid and stirred for 75 minutes at abath temperature of 100° C. Then, the reaction mixture is cooled to roomtemperature, and the solvent is removed in a vacuum. The residue ismixed with water, extracted three times with ethyl acetate, washedneutral, dried on magnesium sulfate and concentrated by evaporation in avacuum. Column chromatographic separation on silica gel with ahexane-ethyl acetate gradient results in 4.17 g of5-[4-(6-chloro-hexyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olwith a melting point of: 193° C.

b)5-[4-(6-Iodo-hexyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol

2.05 g of5-[4-(6-chloro-hexyloxy)-phenyl)-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olis introduced into 70 ml of ethylmethylketone, mixed with 2.60 g ofsodium iodide and stirred for 12 hours at a bath temperature of 100° C.The cooled reaction mixture is concentrated by evaporation in a vacuum,mixed with water and extracted three times with ethyl acetate. Theorganic phase is then washed with sodium thiosulfate solution andsaturated sodium chloride solution. Drying on magnesium sulfate andconcentration by evaporation in a vacuum yields 2.50 g of5-[4-(6-iodo-hexyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol,which is used without further purification in the next stage.

c)5-{4-[6-(4,4,5,5,5-Pentafluoro-pentylthio)-hexyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol

A solution of 1.37 g of 4,4,5,5,5-pentafluoropentylthioacetate in 6 mlof methanol is stirred with 1.1 ml of a 30% methanolic sodium methylatesolution at room temperature for 0.5 hour. This solution is added indrops to a suspension of 2.48 g of5-[4-(6-iodo-hexyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olin 25 ml of methanol and 25 ml of diethyl ether, and it is stirred for 4hours at room temperature. Then, the preparation is concentrated byevaporation in a vacuum, added to water, extracted three times withethyl acetate, washed neutral, dried on magnesium sulfate andconcentrated by evaporation in a vacuum. Recrystallization of the crudeproduct from hexane/diethyl ether yields 2.44 g of5-{4-[6-(4,4,5,5,5-pentafluoro-pentylthio)-hexyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olwith a melting point of: 166° C.

Example 295-{4-[6-(4,4,5,5,5-Pentafluoro-pentanesulfinyl)-hexyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol

2.1 g of5-{4-[6-(4,4,5,5,5-pentafluoro-pentylthio)-hexyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol(Example: 28c) is introduced into 56 ml of methanol and 3.3 ml of water,mixed with 782 mg of sodium periodate and stirred for 12 hours at roomtemperature. Then, the methanol is drawn off in a vacuum, the residue isadded to water, extracted three times with ethyl acetate, washed withsaturated sodium chloride solution, dried on magnesium sulfate andconcentrated by evaporation in a vacuum. 2.13 g of5-{4-[6-(4,4,5,5,5-pentafluoro-pentanesulfinyl)-hexyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olwith a melting point of: 121° C. is obtained.

Example 306-Phenyl-5-{4-[6-(pyridin-2-ylmethanesulfinyl)-hexyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol

1.30 g of6-phenyl-5-{4-[6-(pyridin-2-ylmethylthio)-hexyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol(Example: 25) is introduced into 40 ml of methanol and 2.3 ml of water,mixed with 550 mg of sodium periodate and stirred overnight at roomtemperature. On the following day, it is heated for 6 hours to 40° C.,and stirred again overnight at room temperature. Then, the methanol isdrawn off in a vacuum, the residue is mixed with water, extracted threetimes with ethyl acetate, washed with saturated sodium chloridesolution, dried on magnesium sulfate and concentrated by evaporation ina vacuum. Column chromatographic separation on silica gel with amethylene chloride-methanol gradient yields 464 mg of6-phenyl-5-{4-[6-(pyridin-2-ylmethanesulfinyl)-hexyloxy)-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-olwith a melting point of: 80° C.

Example 316-Phenyl-5-{4-[5-(pyridin-2-ylmethanesulfinyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol

1.86 g of6-phenyl-5-{4-[5-(pyridin-2-ylmethylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol(Example: 24) is introduced into 58 ml of methanol and 3.4 ml of water,mixed with 805 mg of sodium periodate, stirred overnight at roomtemperature and on the following day for 6 hours at 40° C. Then, themethanol is drawn off in a vacuum, the residue is mixed with water,extracted three times with ethyl acetate, washed with saturated sodiumchloride solution, dried on magnesium sulfate and concentrated byevaporation in a vacuum. 2.97 g of crude product, which is preferably bycolumn chromatography with a methylene chloride/methanol gradient isobtained. Recrystallization from methylene chloride/ether yields 635 mgof6-phenyl-5-{4-[5-(pyridin-2-ylmethanesulfinyl)-pentyloxy,]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-olwith a melting point of: 176° C.

Example 325-{4-[5-(Furan-2-ylmethylthio)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol

0.6 ml of furfurylmercaptan in 2 ml of methanol is mixed at roomtemperature drop by drop with 1.1 ml of a 30% methanolic sodiummethylate solution, and it is stirred for 15 more minutes. Then, thesolution is added in drops to a suspension of 1.08 g of5-[4-(5-iodopentyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol(Example: 8j) in 10 ml of methanol, and it is heated for 2 hours to abath temperature of 80° C. For working-up, the reaction mixture isallowed to reach room temperature, stirred into semisaturated sodiumchloride solution, extracted three times with ethyl acetate, washed withsaturated sodium chloride solution, dried on magnesium sulfate andconcentrated by evaporation in a vacuum. Recrystallization from hexaneresults in 920 mg of5-{4-[5-(furan-2-ylmethylthio)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olwith a melting point of: 171° C.

Example 336-Phenyl-5-{4-[5-(thien-2-ylmethylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol

0.24 ml of 2-thienylmethylmercaptan is dissolved in 1 ml of methanol andmixed drop by drop at room temperature with 0.5 ml of 30% methanolicsodium methylate solution. It is stirred for 15 more minutes, beforethis solution is added to a suspension of 524 mg of5-[4-(5-iodopentyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol(Example: 8j) in 5 ml of methanol, and it is heated for 2 hours to abath temperature of 80° C. The reaction mixture that is cooled to roomtemperature is added to semisaturated sodium chloride solution,extracted three times with ethyl acetate, dried on magnesium sulfate andconcentrated by evaporation in a vacuum. Recrystallization from hexaneyields 451 mg of6-phenyl-5-{4-[5-(thien-2-ylmethylthio)-pentyloxy)-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-olwith a melting point of: 178° C.

Examples 34 and 355-{4-[5-(Furan-2-ylmethanesulfinyl)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-oland5-{4-[5-(furan-2-ylmethanesulfonyl)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol

510 mg of5-{4-[5-(furan-2-ylmethylthio)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol(Example; 32) is dissolved in 16 ml of methanol and 0.95 ml of water,mixed with 225 mg of sodium periodate and stirred overnight at roomtemperature. On the following day, 55 mg of sodium periodate is againadded and stirred for 1 hour at 50° C. The cooled reaction mixture isadded to semisaturated sodium chloride solution, extracted three timeswith ethyl acetate, washed with saturated sodium chloride solution,dried on sodium sulfate and concentrated by evaporation in a vacuum.Column chromatographic purification on silica gel with a hexane-ethylacetate gradient results in 498 mg of5-{4-[5-(furan-2-ylmethanesulfinyl)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olwith a melting point of: 168° C. and 16 mg of5-{4-[4-(furan-2-ylmethanesulfonyl)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olwith a melting point of: 186° C.

Examples 36 and 376-Phenyl-5-{4-[5-(thien-2-ylmethanesulfonyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-oland6-phenyl-5-{4-[5-(thien-2-ylmethanesulfinyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol

386 mg of6-phenyl-5-{4-[5-(thien-2-ylmethylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol(Example: 33) is reacted analogously to Examples 34/35. Afterchromatographic purification on silica gel with a hexane-ethyl acetategradient, 28 mg of6-phenyl-5-{4-[5-(thien-2-ylmethanesulfonyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ylwith a melting point of 212° C. and 312 mg of6-phenyl-5-{4-[5-(thien-2-ylmethanesulfinyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-olwith a melting point of: 174-177° C. are obtained.

Example 385-{4-[5-(3,3,4,4,5,5,5-Heptafluoro-pentylthio)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ola)(3,3,4,4,5,5,5-Heptafluoro-pentyl)-(5-{4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl}-phenoxy}-pentyl)-sulfide

404 mg ofS-(5-{4-[6-phenyl-2-tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenoxy}-pentyl)-thioacetate(Example: 12b) in 1 ml of methanol is mixed at room temperature drop bydrop with 0.14 ml of 30% methanolic sodium methylate solution. It isstirred for 30 more minutes at room temperature before 187 mg ofheptafluoro-5-iodopentane in 4 ml of methanol is added in drops. After90 minutes of stirring at room temperature, the preparation is added tosemisaturated sodium chloride solution, extracted three times with ethylacetate, dried on magnesium sulfate and concentrated by evaporation in avacuum. Column chromatographic purification of the residue on silica gelwith a hexane-ethyl acetate gradient yields 120 mg of(3,3,4,4,5,5,5-heptafluoro-pentyl)-(5-{4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenoxy}-pentyl)-sulfide.

b)5-{4-[5-(3,3,4,4,5,5,5-Heptafluoro-pentylthio)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol

110 mg of(3,3,4,4,5,5,5-heptafluoro-pentyl)-(5-{4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenoxy}-pentyl)-sulfideis dissolved in 2.5 ml of methanol and 0.25 ml of water, mixed with 100mg of oxalic added in drops and stirred for 2 hours at 50° C. The cooledreaction mixture is mixed with about 5 ml of water and stirred for 30minutes. The deposited precipitation is suctioned off, thoroughlyrewashed and dried in a vacuum. 86 mg of5-{4-[5-(3,3,4,4,5,5,5-heptafluoro-penthylthio)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olwith a melting point of 156° C. is obtained.

Example 395-{4-[2-(2-Hydroxy-ethylamino)-ethoxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol

A solution of 1 g of5-[4-(2-iodoethyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol(Example 11c) in 10 ml of methanol is refluxed with 1.24 ml of2-aminoethanol for 0.5 hour at a bath temperature of 160° C. Then, it isadded to sodium bicarbonate solution, extracted three times with ethylacetate/methanol (4/1), washed neutral, dried on sodium sulfate,concentrated by evaporation in a vacuum and recrystallized from ethylacetate/methanol. 621 mg of5-{4-[2-(2-hydroxy-ethylamino)-ethoxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olis obtained as crystals with a melting point of 176-178° C.

Starting Material

1-Iodo-3-(4,4,5,5,5-pentafluoropentylthio)-propane

1-iodo-5-(4,4,5,5,5-pentafluoropentanesulfinyl)-pentane

1-iodo-5-(4,4,5,5,5-pentafluoropentanesulfonyl)-pentaneN-butyl-2-iodoethanesulfinyl-N-methyl-acetamide

Example 405-{4-[5-(4-Fluoro-butylthio)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ola)(4-Fluoro-butyl)-(5-{4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenoxy}-pentyl)-sulfide

500 mg ofS-(5-{4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenoxy}-pentyl)-thioacetate(Example: 12b) is dissolved in 5 ml of tetrahydrofuran and 7.4 ml ofmethanol and mixed at room temperature drop by drop with 0.2 ml of a 30%methanolic sodium methylate solution. After the addition has beencompleted, it is stirred for 30 more minutes at room temperature before0.15 ml of 1-bromo-4-fluorobutane is added in drops at the sametemperature. After 90 minutes, the reaction mixture is mixed withsemisaturated sodium chloride solution, extracted three times with ethylacetate, washed neutral, dried on magnesium sulfate and concentrated byevaporation in a vacuum. Column chromatographic purification on silicagel with a hexane-ethyl acetate gradient yields 344 mg of(4-fluoro-butyl)-(5-{4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenoxy}-pentyl)-sulfideas a foam.

b)5-{4-[5-(4-Fluoro-butylthio)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol

336 mg of(4-fluoro-butyl)-(5-{4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenoxy]-pentyl)-sulfideis dissolved in 9 ml of methanol, 10 ml of tetrahydrofuran and 0.92 mlof water, mixed with 368 mg of oxalic added in drops and stirred at 50°C. After 2 hours, the further addition of 184 mg of oxalic acid iscarried out. After 24 hours, the reaction mixture is cooled to roomtemperature, mixed with 25 ml of water and stirred for 30 minutes. Thedeposited precipitation is suctioned off and dried. 275 mg of5-{4-[5-(4-fluoro-butylthio)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olwith a melting point of 163° C. is obtained.

Example 415-{4-[5-(4-Fluoro-butanesulfinyl)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol

181 mg of5-{4-[5-(4-fluoro-butylthio)-pentyloxy3-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol(Example: 40b) is dissolved in 6 ml of methanol and 0.5 ml of water,mixed with 81 mg of sodium periodate and stirred for 2 hours at 50° C.For working-up, the reaction mixture is mixed with dilute sodiumchloride solution, extracted three times with methylene chloride, washedwith water, dried on magnesium sulfate and concentrated by evaporationin a vacuum. The residue is absorptively precipitated with 10 ml ofether, the solid is suctioned off and dried. 173 mg of5-{4-[5-(4-fluoro-butanesulfinyl)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olwith a melting point of 233° C. is obtained.

Example 426-Phenyl-5-{4-[5-(4,4,4-trifluoro-butylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ola)(5-{4-[6-Phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenoxy}-pentyl)-(4,4,4-trifluoro-butyl)-sulfide

500 mg ofS-(5-{4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenoxy}-pentyl)-thioacetate(Example: 12b) is dissolved in 5 ml of tetrahydrofuran and 7.4 ml ofmethanol and mixed at room temperature drop by drop with 0.2 ml of a 30%methanolic sodium methylate solution. After the addition is completed,it is stirred for 30 more minutes at room temperature before 325 mg of4,4,4-trifluoro-1-iodobutane is added at the same temperature. After 90minutes, the reaction mixture is mixed with semisaturated sodiumchloride solution, extracted three times with ethyl acetate, washedneutral, dried on magnesium sulfate and concentrated by evaporation in avacuum.

Column chromatographic purification on silica gel with a hexane-ethylacetate gradient yields 314 mg of(5-{4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl}-phenoxy}-pentyl)-(4,4,4-trifluoro-butyl)-sulfideas a foam.

b)6-Phenyl-5-{4-[5-(4,4,4-trifluoro-butylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol

310 mg of(5-{4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenoxy}-pentyl)-(4,4,4-trifluoro-butyl)-sulfideis dissolved in 8 ml of methanol, 7 ml of tetrahydrofuran and 0.8 ml ofwater, mixed with 319 mg of oxalic acid and stirred for 3 hours at 50°C. Then, the reaction mixture is cooled to room temperature, mixed with25 ml of water and stirred for 30 minutes. The deposited precipitate issuctioned off and dried. 243 mg of6-phenyl-5-{4-[5-(4,4,4-trifluoro-butylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-olwith a melting point of 168° C. is obtained.

Example 436-Phenyl-5-{4-[5-(4,4,4-trifluoro-butanesulfinyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol

109 mg of6-phenyl-5-{4-[5-(4,4,4-trifluoro-butylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-olis dissolved at 0° C. in 4 ml of tetrahydrofuran, mixed with 44 mg ofm-chloro-perbenzoic acid and stirred at 0° C. After 15 minutes, 15 mg ofm-chloro-perbenzoic acid is again added, and the reaction mixture isstirred for another 15 minutes at 0° C. For working-up, the reactionmixture is added to 10% sodium thiosulfate solution, extracted threetimes with methylene chloride, washed with water, dried on magnesiumsulfate and concentrated by evaporation in a vacuum. Columnchromatographic purification on silica gel with a methylenechloride-methanol gradient results in 82 mg of6-phenyl-5-{4-[5-(4,4,4-trifluoro-butanesulfinyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-olwith a melting point of 145° C.

Example 445-(4-{5-[Methyl-(4,4,5,5,5-pentafluoropentyl)-amino]-pentyloxy}-phenyl)-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ola)methyl-(5-{4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenoxy}-pentyl)-amine

914 mg of2-{5-[4-(5-iodopentyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy}tetrahydropyran(Example: 12a) is dissovled in a pressure pipe in 5 ml oftetrahydrofuran and about 800 mg of methylamine is condensed at −15° C.Then, the closed pressure pipe is allowed to stand overnight at roomtemperature. For working-up, the vessel is cooled to −15° C., excessmethylamine is evaporated in a nitrogen stream at room temperature, thepreparation is added to dilute sodium chloride solution, extracted threetimes with methylene chloride, dried on magnesium sulfate andconcentrated by evaporation in a vacuum. 809 mg ofmethyl-(5-{4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenoxy}-pentyl)-amineis obtained as a crude product, which is used without furtherpurification in the next stage.

b)Methyl-(4,4,5,5,5-pentafluoropentyl)-(5-{4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenoxy}-pentyl)-amine

809 mg ofmethyl-(5-{4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenoxy}-pentyl)amineis dissolved in 15 ml of N-methyl-pyrrolidone, mixed in portions with atotal of 698 mg of 4,4,5,5,5-pentafluoro-pentyltosylate and stirred for3 hours at 80° C. After the preparation is cooled to room temperature,the reaction mixture is added to dilute sodium chloride solution,extracted three times with diethyl ether, dried on magnesium sulfate andconcentrated by evaporation in a vacuum. Column chromatographicpurification on silica gel with a methylene chloride-methanol gradientresults in 1.8 g ofmethyl-(4,4,5,5,5-pentafluoropentyl)-(5-{4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenoxy}-pentyl)-amine,which is contaminated with N-methyl-pyrrolidone.

c)5-(4-{5-[Methyl-(4,4,5,5,5-pentafluoropentyl)-amino]-pentyloxy}-phenyl)-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol

1.8 g ofmethyl-(4,4,5,5,5-pentafluoropentyl)-(5-{4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenoxy}-pentyl)-amine,which is contaminated with N-methyl-pyrrolidone, is dissolved in 25 mlof methanol and 2.5 ml of water, mixed with 1.85 g of oxalic acid andstirred for 90 minutes at 50° C. After the reaction mixture is cooled,it is added to dilute sodium bicarbonate solution, extracted three timeswith diethyl ether, washed with water, dried on magnesium sulfate andconcentrated by evaporation in a vacuum. The residue is put on a columnon silica gel with a methylene chloride-methanol gradient. 214 mg of5-(4-{5-[methyl-(4,4,5,5,5-pentafluoropentyl)-amino]-pentyloxy}-phenyl)-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olis obtained.

Production of the Starting Material 4,4,5,5,5-Pentafluoro-pentyltosylate

6.4 g of p-toluenesulfonyl chloride is introduced into 10 ml ofpyridine, mixed drop by drop with 5.44 g of4,4,5,5,5-pentafluoro-pentan-1-ol at 0° C. and after the addition iscompleted, it is stirred for 2 hours at room temperature. Forworking-up, the preparation is taken up in ice-cold 2N hydrochloricacid, extracted three times with diethyl ether, washed with saturatedsodium chloride solution, dried on magnesium sulfate and concentrated byevaporation in a vacuum. Column chromatographic purification on silicagel with a hexane-ethyl acetate gradient yields 8.7 g of4,4,5,5,5-pentafluoro-pentyltosylate as a clear liquid.

Example 455-[4-(5-Benzylthio-pentyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ola)Benzyl-(5-{4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-S-yl]-phenoxy}-pentyl)-sulfide

1.5 g ofS-(5-{4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenoxy{-pentyl)-thioacetate(Example: 12b) is dissolved in 10 ml of tetrahydrofuran and 22 ml ofmethanol and mixed drop by drop at room temperature with 0.6 ml of a 30%methanolic sodium methylate solution. After the addition is completed,it is stirred for 30 more minutes at room temperature, before 0.5 ml ofbenzylbromide is added in drops at the same temperature. After 2 hours,the reaction mixture is mixed with dilute sodium chloride solution,extracted three times with ethyl acetate, washed neutral, dried onmagnesium sulfate and concentrated by evaporation in a vacuum. Columnchromatographic purification on silica gel with a hexane-ethyl acetategradient yields 1.12 g ofbenzyl-(5-{4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenoxy}-pentyl)-sulfideas a foam.

b)5-[4-(5-Benzylthio-pentyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol

1.12 g ofbenzyl-(5-{4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenoxy}{-pentyl)-sulfideis dissolved in 27 ml of methanol, 3 ml of tetrahydrofuran and 2.7 ml ofwater, mixed with 1.16 g of oxalic acid and stirred for 3 hours at 50°C. Then, the reaction mixture is cooled to room temperature, mixed with5 ml of water and stirred for 5 minutes. The deposited precipitate issuctioned off and dried. 855 mg of5-[4-(5-benzylthio-pentyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olwith a melting point of: 178-186° C. is obtained.

Example 465-[4-(5-Benzylsulfinyl-pentyloxy)-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol

555 mg of5-[4-(5-benzylthio-pentyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol(Example: 45) is dissolved in 17 ml of methanol, 15 ml of ethyl acetateand 1 ml of water, mixed with 241 mg of sodium periodate and stirredfirst at room temperature and later for 3 hours at 50° C. Forworking-up, the reaction mixture is mixed with dilute sodium chloridesolution, extracted three times with methylene chloride, washed withwater, dried on magnesium sulfate and concentrated by evaporation in avacuum. By column chromatographic purification on silica gel with ahexane-ethyl acetate gradient, 469 mg of5-[4-(5-benzylsulfinyl-pentyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olwith a melting point of: 196° C. is obtained.

Example 475-{4-[5-(4-Methyl-benzylthio)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ola)(4-Methyl-benzyl)-(5-{4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenoxy}-pentyl)-sulfide

1.5 g ofS-(5-{4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenoxy}-pentyl)-thioacetate(Example: 12b) is dissolved in 5 ml of tetrahydrofuran and 20 ml ofmethanol and mixed drop by drop at room temperature with 0.6 ml of a 30%methanolic sodium methylate solution. After the addition is completed,it is stirred for 30 more minutes at room temperature before 757 mg of4-methyl-benzylbromide in 5 ml of tetrahydrofuran is added in drops atthe same temperature. After 2 hours, the reaction mixture is mixed withdilute sodium chloride solution, extracted three times with ethylacetate, washed neutral, dried on magnesium sulfate and concentrated byevaporation in a vacuum. Column chromatographic purification on silicagel with a hexane-ethyl acetate gradient yields 1.24 g of(4-methyl-benzyl)-(5-{4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenoxy}-pentyl)-sulfideas a foam.

b)5-{4-[5-(4-Methyl-benzylthio)-pentyloxy]-phenyl}=6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol

250 mg of(4-methyl-benzyl)-(5-{4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenoxy}-pentyl)-sulfideis dissolved in 6 ml of methanol, 1 ml of tetrahydrofuran and 0.6 ml ofwater, mixed with 258 mg of oxalic acid and stirred for 3 hours at 50°C. Then, the reaction mixture is cooled to room temperature, mixed with5 ml of water and stirred for 5 minutes. The deposited precipitate issuctioned off and dried. 196 mg of5-{4-[5-(4-methyl-benzylthio)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olwith a melting point of 165-169° C. is obtained.

Example 485-{4-[5-(4-Methyl-benzylsulfinyl)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol

600 mg of5-{4-[5-(4-methyl-benzylthio)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol(Example: 47b) is dissolved in 18 ml of methanol, 15 ml of ethyl acetateand 1 ml of water, mixed with 252 mg of sodium periodate and stirredfirst at room temperature and later for 3 hours at 50° C. Forworking-up, the reaction mixture is mixed with dilute sodium chloridesolution, extracted three times with methylene chloride, washed withwater, dried on magnesium sulfate and concentrated by evaporation in avacuum. By column chromatographic purification on silica gel with ahexane-ethyl acetate gradient, 248 mg of5-{4-[5-(4-methyl-benzylsulfinyl)-pentyloxy3-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olis obtained.

Example 496-Phenyl-5-{4-[5-(4-trifluoromethyl-benzylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ola)(5-{4-[6-Phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenoxy}-pentyl)-(4-trifluoromethyl-benzyl)-sulfide

1.5 g ofS-(5-{4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenoxy}-pentyl)-thioacetate(Example: 12b) is dissolved in 10 ml of tetrahydrofuran and 20 ml ofmethanol and mixed drop by drop at room temperature with 0.6 ml of a 30%methanolic sodium methylate solution. After the addition is completed,it is stirred for 30 more minutes at room temperature before 977 mg of4-(trifluoromethyl)benzylbromide in 5 ml of tetrahydrofuran is added indrops at the same temperature. After 2 hours, the reaction mixture ismixed with dilute sodium chloride solution, extracted three times withethyl acetate, washed neutral, dried on magnesium sulfate andconcentrated by evaporation in a vacuum.

Column chromatographic purification on silica gel with a hexane-ethylacetate gradient yields 1.15 g of(5-{4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenoxy}-pentyl)-(4-trifluoromethyl-benzyl)-sulfideas a foam.

b)6-Phenyl-5-{4-[5-(4-trifluoromethyl-benzylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol

1.14 g of(5-{4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenoxy}-pentyl)-(4-trifluoromethyl-benzyl)-sulfideis dissolved in 27 ml of methanol, 3 ml of tetrahydrofuran and 2.7 ml ofwater, mixed with 1.16 g of oxalic acid and stirred for 3 hours at 50°C. Then, the reaction mixture is cooled to room temperature, mixed with5 ml of water, and stirred for 5 minutes. The deposited precipitate issuctioned off and dried. 933 mg of6-phenyl-5-{4-[5-(4-trifluoromethyl-benzylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-olwith a melting point of 147° C. is obtained.

Example 506-Phenyl-5-{4-[5-(4-trifluoromethyl-benzylsulfinyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol

600 mg of6-phenyl-5-{4-[5-(4-trifluoromethyl-benzylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-yl(Example: 49b) is dissolved in 16 ml of methanol, 15 ml of ethyl acetateand 1 ml of water, mixed with 230 mg of sodium periodate and stirredfirst at room temperature and later for 3 hours at 50° C. Forworking-up, the reaction mixture is mixed with dilute sodium chloridesolution, extracted three times with methylene chloride, washed withwater, dried ion magnesium sulfate and concentrated by evaporation in avacuum. By column chromatographic purification on silica gel with ahexane-ethyl acetate gradient, 494 mg of6-phenyl-5-{4-[5-(4-trifluoromethyl-benzylsulfinyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-27-olis obtained.

Example 516-Phenyl-5-[4-(5-phenylthio-pentyloxy)-phenyl]-8,9-dihydro-7H-benzocyclohepten-2-ola)Phenyl-(5-{4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenoxy}-pentyl)-sulfide

1.0 g of2-{5-[4-(5-iodopentyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydropyran(Example: 12a) is dissolved in 5 ml of tetrahydrofuran and mixed at roomtemperature with 0.34 ml of 30% aqueous potassium hydroxide solution and0.17 ml of thiophenol. Then, it is stirred for 4 hours at 90° C. Forworking-up, the reaction mixture is allowed to reach room temperature,diluted with diethyl ether, washed three times with water, dried onmagnesium sulfate and concentrated by evaporation in a vacuum. Columnchromatographic purification on silica gel with a hexane-ethyl acetategradient yields 816 mg ofphenyl-(5-{4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenoxy}-pentyl-sulfideas a foam.

b)6-Phenyl-5-[4-(5-phenylthio-pentyloxy)-phenyl]-8,9-dihydro-7H-benzocyclohepten-2-ol

816 mg ofphenyl-(5-{4-[6-phenyl-2-(tetrahydropyran-2-yloxy-8,9-dihydro-7H-benzocyclohepten-5-yl}-phenoxy}-pentyl)-sulfideis dissolved in 20 ml of methanol, 5 ml of tetrahydrofuran and 2 ml ofwater, mixed with 890 mg of oxalic acid and stirred for 90 minutes at50° C. Then, the reaction mixture is cooled to room temperature, mixedwith 25 ml of water and stirred for 30 minutes. The depositedprecipitate is suctioned off and dried. 670 mg of6-phenyl-5-[4-(5-phenylthio-pentyloxy)-phenyl]-8,9-dihydro-7H-benzocyclohepten-2-ylwith a melting point of 192° C. is obtained.

Examples 52 and 536-Phenyl-5-[4-(5-phenylsulfinyl-pentyloxy)-phenyl]-8,9-dihydro-7H-benzocyclohepten-2-oland6-phenyl-5-[4-(5-phenylsulfonyl-pentyloxy)-phenyl]-8,9-dihydro-7H-benzocyclohepten-2-ol

109 mg of6-phenyl-5-[4-(5-phenylthio-pentyloxy)-phenyl]-8,9-dihydro-7H-benzocyclohepten-2-ol(Example: 51b) is introduced at 0° C. into 8 ml of methylene chlorideand mixed with 57 mg of m-chloroperbenzoic acid. After 1.5 hours ofstirring under cold conditions, the reaction is completed by addingsodium thiosulfate solution. Then, the preparation is mixed withsaturated sodium bicarbonate solution, extracted three times withmethylene chloride, washed neutral, dried on magnesium sulfate andevaporated to the dry state in a vacuum. Preparative thin-layerchromatography with a hexane-ethyl acetate mixture yields 22 mg of6-phenyl-5-[4-(5-phenylsulfonyl-pentyloxy)-phenyl]-8,9-dihydro-7H-benzocyclohepten-2-olwith a melting point of 162° C. and 75 mg of6-phenyl-5-[4-(5-phenylsulfinyl-pentyloxy)-phenyl]-8,9-dihydro-7H-benzocyclohepten-2-ol.

Example 545-{4-[5-(4-tert-Butyl-phenylthio)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ola)(4-tert-Butyl-phenyl)-5-{4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenoxy}-pentyl)-sulfide

1.5 g of2-{5-[4-(5-iodopentyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydropyran(example: 12a) is dissolved in 7.5 ml of tetrahydrofuran and mixed atroom temperature with 0.51 ml of of 30% aqueous potassium hydroxidesolution and 409 mg of 4-tert-butylthiophenol. Then, it is stirred for 1hour at 90° C. For working-up, the reaction mixture is allowed to reachroom temperature, diluted with diethyl ether, washed twice with water,dried on magnesium sulfate and concentrated by evaporation in a vacuum.Column chromatographic purification on silica gel with a hexane-diehtylether gradient yields 1.35 g of(4-tert-butyl-phenyl)-(5-{4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenoxy}-pentyl)-sulfideas a foam.

b)5-{4-[5-(4-tert-Butyl-phenylthio)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol

1.34 g of(4-tert-butyl-phenyl)-(5-{4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenoxy}-pentyl)-sulfideis dissovled in 30 ml of methanol, 3 ml of tetrahydrofuran and 3 ml ofwater, mixed with 1.33 g of oxalic acid and stirred for 5 hours at 50°C. Then, the reaction mixture is cooled to room temperature, mixed with10 ml of water and stirred for 15 minutes. The deposited precipitate issuctioned off and dried. Preparative column chromatography on silica gelwith a hexane-ethyl acetate gradient yields 946 mg of5-{4-[5-(4-tert-butyl-phenylthio)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-olwith a melting point of 139° C.

Examples 55 and 565-{4-[5-(4-tert-Butyl-phenylsulfinyl)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-oland5-{4-[5-(4-tert-butyl-phenylsulfonyl)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol

450 mg of5-{4-[5-(4-tert-butyl-phenylthio)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol(Example: 54b) is introduced at 0° C. in 30 ml of methylene chloride andmixed with 206 mg of m-chloroperbenzoic acid. After 1 hour of stirringunder cold conditions, the preparation is mixed with saturated sodiumbicarbonate solution, extracted three times with methylene chloride,washed neutral, dried on magnesium sulfate and evaporated to the drystate in a vacuum. Preparative column chromatography on silica gel witha hexane-ethyl acetate gradient yields 32 mg of5-{4-[5-(4-tert-butyl-phenylsulfonyl)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-oland 412 mg of5-{4-[5-(4-tert-butyl-phenylsulfinyl)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol.

Example 576-Phenyl-5-{4-[5-(4-trifluoromethyl-phenylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ola)(5-{4-[6-Phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenoxy}-pentyl)-(4-trifluoromethyl-phenyl)-sulfide

1.5 g of2-{5-[4-(5-iodopentyloxy)-phenyl]-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-yloxy}-tetrahydropyran(example: 12a) is dissolved in 7.5 ml of tetrahydrofuran and mixed atroom temperature with 0.51 ml of 30% aqueous potassium hydroxidesolution and 438 mg of 4-(trifluoromethyl)-thiophenol. Then, it isstirred for 1 hour at 90° C. For working-up, the reaction mixture isallowed to reach room temperature, diluted with diethyl ether, washedtwice with water, dried on magnesium sulfate and concentrated byevaporation in a vacuum. Column chromatographic purification on silicagel with a hexane-diehtyl ether gradient yields 1.28 g of(5-{4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl)-phenoxy}-pentyl)-(4-trifluoromethyl-phenyl)-sulfide.

b)6-Phenyl-5-{4-[5-(4-trifluoromethyl-phenylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol

1.28 g of(5-{4-[6-phenyl-2-(tetrahydropyran-2-yloxy)-8,9-dihydro-7H-benzocyclohepten-5-yl]-phenoxy}-pentyl)-(4-trifluoromethyl-phenyl)-sulfideis dissovled in 29 ml of methanol, 3 ml of tetrahydrofuran and 3 ml ofwater, mixed with 1.25 g of oxalic acid and stirred for 5 hours at 50°C. Then, the reaction mixture is cooled to room temperature, mixed with10 ml of water and stirred for 15 minutes. The deposited precipitate issuctioned off and dried. Recrystallization from ethyl acetate yields 890mg of6-(phenyl-5-{4-[5-(4-trifluoromethyl-phenylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-olwith a melting point of: 189° C.

Examples 58 and 596-Phenyl-5-{4-[5-(4-trifluoromethyl-phenylsulfinyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-oland6-phenyl-5-{4-[5-(4-trifluoromethyl-phenylsulfonyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol

425 mg of6-phenyl-5-{4-[5-(4-trifluoromethyl-phenylthio)-pentyloxy[-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol(Example: 57b) is introduced at 0° C. into 28 ml of methylene chlorideand mixed with 190 mg of m-chloroperbenzoic acid. After 1 hour ofstirring under cold conditions, the preparation is mixed with saturatedsodium bicarbonate solution, extracted three times with methylenechloride, washed neutral, dried on magnesium sulfate and evaporated tothe dry state in a vacuum. Preparative column chromatography on silicagel with a hexane-ethyl acetate gradient yields 71 mg of6-phenyl-5-{4-(5-(4-trifluoromethyl-phenylsulfonyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-olwith a melting point of: 187° C. and 325 mg of6-phenyl-5-{4-[5-(4-trifluoromethyl-phenylsulfinyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol.

1. A benzocycloheptene of formula I

in which R¹ and R², independently of one another, are each H, a hydroxygroup, an optionally substituted C₁-C₁₀ alkoxy group, an optionallysubstituted C₁-C₁₀ alkanoyloxy group or an optionally substituted C₇-C₁₅aroyloxy group; Y is a side chain —A-B-Z; A is a direct bond or anoxygen atom; B is a straight-chain or branched-chain, optionallysubstituted alkylene, alkeneylene or alkinylene group with up to 10carbon atoms; Z is a group -D-SO_(x)-E-G, an amino group —NR⁷R⁸ or asubstituent G; D is a direct bond or a group —NR³(R⁴—); R³ is astraight-chain or branched-chain alkyl, alkenyl or alkinyl group with upto 10 carbon atoms; R⁴ is a straight-chain or branched-chain, optionallysubstituted alkylene, alkenylene or alkinylene group with up to 10carbon atoms, the nitrogen atom is optionally incorporated in a 4- to7-membered ring system; x is 0, 1 or 2; E is a straight-chain orbranched-chain, optionally substituted alkylene, alkenylene oralkinylene group with up to 10 carbon atoms; G is a partially orcompletely fluorinated straight-chain or branched-chain alkyl group withup to 5 carbon atoms, an optionally substituted aryl or heteroarylradical, a carbamoyl radical —C(O)—NR⁵R⁶, a halogen atom or a hydrogenatom, R⁵, R⁶, R⁷ and R⁸, independently of one another, are each H, astraight chain or branched-chain, optionally partially fluorinatedalkyl, alkenyl or alkinyl radical with up to 14 carbon atoms, which isoptionally interrupted by one to three heteroatoms —O— and —S— orgroupings —NR⁹—, an aryl or heteroaryl radical that is optionallysubstituted in one or two places, a C₃-C₁₀ cycloalkyl radical that isoptionally substituted in one or two places, a C₄-C₁₅ cycloalkylalkylradical that is optionally substituted in one or two places, a C₇-C₂₀aralkyl radical that is optionally substituted in one or two places, aheteroaryl-C₁-C₈ alkyl radical that is optionally substituted in one ortwo places, an optionally substituted aminoalkyl radical, a biphenyleneradical or a radical of formula —C(O)R¹⁰, R⁵, R⁶, R⁷ and R⁸ with thenitrogen atom, to which they are bonded, optionally form a saturated orunsaturated heterocycle with 5 or 6 chain links, which optionallycontains one or two additional heteroatoms, selected from nitrogen,oxygen and sulfur, and optionally is substituted; R⁹ is H or C₁₋₃ alkyl;and R¹⁰ is H, a straight chain or branched-chain, optionally partiallyfluorinated alkyl, alkenyl or alkinyl radical with up to 14 carbonatoms, which is optionally interrupted by one to three heteroatoms —O—and —S— or groupings —NR⁹—, an aryl or heteroaryl radical that isoptionally substituted in one or two places, a C₃-C₁₀ cycloalkyl radicalthat is optionally substituted in one or two places, a C₄-C₁₅cycloalkylalkyl radical that is optionally substituted in one or twoplaces, a C₇-C₂₀ aralkyl radical that is optionally substituted in oneor two places, a heteroaryl-C₁-C₈ alkyl radical that is optionallysubstituted in one or two places an optionally substituted aminoalkylradical, or a biphenylene radical: wherein in -A-B-Z, if A is an oxygenatom and Z is G,G cannot be a hydrogen atom or a halogen atom, or if Ais for an oxygen atom and Z is stands for an amino group —NR⁷R⁸, inwhich are R⁷ and R⁸ in each case mean a methyl group or together withthe nitrogen atom form a pyrrolidine ring, B has at least 3 carbonatoms, or if B is —C₂H₄— and Z is —NR⁷R⁸, then R⁷ and R⁸ are not thesame or together form a heterocycle with the N atom; or aphysiologically compatible addition salt thereof with an organic orinorganic acid; and wherein said compound contains at least oneheterocyclic group.
 2. A compound according to claim 1, in which R¹and/or R² is a hydrogen atom.
 3. A compound according to claim 1, inwhich A is an oxygen atom.
 4. A compound according to claim 1, in whichB is a straight-chain alkylene chain with 1 to 6 carbon atoms.
 5. Acompound according to claim 1, in which side chain Y is selected fromthe following side chains —O—(CH₂)₅ S(CH₂)₃C₂F₅ —O—(CH₂)₅ SO(CH₂)₃C₂F₅—O—(CH₂)₅SO₂(CH₂)₃C₂F₅ —O—(CH₂)₂—N(CH₃)—(CH₂)₃—S—(CH₂)₃C₂F₅—O—(CH₂)₂—N(CH₃)—(CH₂)₃—SO—(CH₂)₃C₂F₅—O—(CH₂)₅S(CH₂)—C(O)N(CH₃)—(CH₂)₃CH₃—O—(CH₂)₅SO(CH₂)—C(O)N(CH₃)—(CH₂)₃CH₃ —O—(CH₂)₂—NH(CH₂)OH—O—(CH₂)₂—N(CH₃)—(CH₂)₂—SO(CH₂)—C(O)N(CH₃)—(CH₂)₃CH₃—O—(CH₂)₆S(CH₂)—C(O)N(CH₃)—(CH₂)₃CH₃—O—(CH₂)₆SO(CH₂)—C(O)N(CH₃)—(CH₂)₃CH₃ —O—CH₃ —O—(CH₂)₅—F —O—(CH₂)₄—F—O—(CH₂)₃—F —O—(CH₂)₂—F —O—(CH₂)₅—Cl —O—(CH₂)₄—Cl —O—(CH₂)₃—Cl—O—(CH₂)₂—Cl —O—(CH₂)₆S(CH₂)₃C₂F₅ —O—(CH₂)₆SO(CH₂)₃C₂F₅—O—(CH₂)₆SO(CH₂)-2-Pyridyl —O—(CH₂)₆SO(CH₂)-2-Pyridyl—O—(CH₂)₅S(CH₂)₂C₃F₇ —O—(CH₂)₂-1-Pyrrolidinyl —O—(CH₂)₄S(CH₂)₃C₂F₅—O—(CH₂)₄SO(CH₂)₃C₂F₅ —O—(CH₂)₄SO₂(CH₂)₃C₂F₅ —O—(CH₂)₄S(CH₂)-2-Pyridyl—O—(CH₂)₄SO(CH₂)-2-Pyridyl —O—(CH₂)₅S(CH₂)-2-Pyridyl—O—(CH₂)₅SO(CH₂)-2-Pyridyl —O—(CH₂)₆S(CH₂)-2-Pyridyl—O—(CH₂)₆SO(CH₂)-2-Pyridyl —O—(CH₂)₅S(CH₂)-2-Furyl—O—(CH₂)₅SO(CH₂)-2-Furyl —O—(CH₂)₅SO₂(CH₂)-2-Furyl—O—(CH₂)₅S(CH₂)-2-Thienyl —O—(CH₂)₅SO(CH₂)-2-Thienyl —O—(CH₂)₅S(CH₂)₄—F—O—(CH₂)₅SO(CH₂)₄—F —O—(CH₂)₅S(CH₂)₃—CF₃ —O—(CH₂)₅ SO(CH₂)₃—CF₃—O—(CH₂)₅—N(CH₃)—(CH₂)₃—C₂F₅ —O—(CH₂)₅S(CH₂)-Phenyl—O—(CH₂)₅SO(CH₂)-2-Phenyl —O—(CH₂)₅S(CH₂)-p-Tolyl—O—(CH₂)₅SO(CH₂)-p-Tolyl —O—(CH₂)₅S(CH₂)-p-CF₃-Phenyl—O—(CH₂)₅SO(CH₂)-p-CF₃-Phenyl —O—(CH₂)₅S-Phenyl —O—(CH₂)₅SO-Phenyl—O—(CH₂)₅S-(p-Tolyl) —O—(CH₂)₅SO-(p-Tolyl) —O—(CH₂)₅S-(p-CF₃-Phenyl)—O—(CH₂)₅SO-(p-CF₃-Phenyl) —O—(CH₂)₂—N(CH₃)₂.
 6. A compound according toclaim 1, in which side chain Y is selected from the following sidechains —(CH₂)₅N(CH₃)(CH₂)₃C₂F₅ —(CH₂)₅N(CH₃)(CH₂)₆C₂F₅—(CH₂)₅N(CH₃)(CH₂)₇C₂F₅ —(CH₂)₅N(CH₃)(CH₂)₈C₂F₅ —(CH₂)₆N(CH₃)(CH₂)₆C₂F₅—(CH₂)₆N(CH₃)(CH₂)₇C₂F₅ —(CH₂)₆N(CH₃)(CH₂)₈C₂F₅ —(CH₂)₅N(CH₃)(CH₂)₂C₄F₉—(CH₂)₅N(CH₃)(CH₂)₃C₆F₁₃ —(CH₂)₅N(CH₃)(CH₂)₃C₈F₁₇—(CH₂)₅N(CH₃)(CH₂)₆C₄F₉ —(CH₂)₅N(CH₃)(CH₂)₆C₆F₁₃—(CH₂)₅N(CH₃)(CH₂)₆C₈F₁₇ —(CH₂)₅N(CH₃)H —(CH₂)₅N(CH₃)(CH₂)₉H—(CH₂)₅-1-Pyrrolidinyl —(CH₂)₉S(CH₂)₃C₂F₅ —(CH₂)₉SO(CH₂)₃C₂F₅—(CH₂)₉SO₂(CH₂)₃C₂F₅.
 7. A compound according to claim 1, in which sidechain Y is selected from the partial formula

wherein a is 4, 5 or 6, b is 0, 1 or 2, c is 0, 1 or 2, R^(x) is ahydrogen atom or a C₁₋₅ alkyl group, R^(y) and R^(z) are each a hydrogenatom, or R^(x) and R^(y) together are an alkylene group —(CH₂)_(d)— inwhich d is 2, 3, 4 or 5, and R² is a hydrogen atom, or R^(x) and R^(z)together are an alkylene group —(CH₂)_(e)— in which e is 2, 3 or 4 andR^(y) is a hydrogen atom, and U is ethyl or ethyl that is fluorinated inone to five places, or the terminal substituent —(CH₂)₃—U in the sidechain is replaced by an optionally substituted aryl or heteroarylradical, which is bonded directly or via a mono-, di- or trimethylenegroup to the sulfur atom.
 8. A compound according to claim 7, in which Yis the side chain —(CH₂)₅N(CH₃)(CH₂)₃S(CH₂)₃C₂F₅.
 9. A compoundaccording to claim 7, in which Y is the side chain(CH₂)₅N(R⁵)(CHR⁶)CH₂S(CH₂)₃C₂F₅ with R⁵+R⁶ being —(CH₂)₃—.
 10. Acompound according to claim 1 wherein said compound is:6-phenyl-5-{4-[4-(pyridin-2-ylmethylthio)-butyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol,6-phenyl-5-{4-[5-(pyridin-2-ylmethylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol,6-phenyl-5-{4-[6-(pyridin-2-ylmethiolthio)-hexyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol,6-phenyl-5-{4-[4-(pyridin-2-ylmethanesulfiny)-butyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol,6-phenyl-5-{4-[6-(pyridin-2-ylmethanesulfinyl)-hexyloxy]-phenyl]-8,9-dihydro-7H-benzocyclohepten-2-ol,6-phenyl-5-{4-[5-(pyridin-2-ylmethanesulfinyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol,5-{4-[5-(furan-2-ylmethylthio)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol,6-phenyl-5-{4-[5-(thien-2-ylmethylthio)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol,5-{4-[5-(furan-2-ylmethanesulfinyl)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol,5-{4-[5-(furan-2-ylmethanesulfonyl)-pentyloxy]-phenyl}-6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol,6-phenyl-5-{4-[5-(thien-2-ylmethanesulfonyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol,6-phenyl-5-{4-[5-(thien-2-ylmethanesulfinyl)-pentyloxy]-phenyl}-8,9-dihydro-7H-benzocyclohepten-2-ol,or a physiologically compatible addition salt thereof with an organic orinorganic acid
 11. A pharmaceutical composition comprising at least onecompound according to claim 1 and a pharmaceutically compatible vehicle.12. A method for preparing a pharmaceutical composition comprisingadmixing a compound according to claim 1 and a pharmaceuticallycompatible vehicle.
 13. A compound according to claim 1, in which Y isthe side chain —(CH₂)₅N(CH₃)(CH₂)₃S(CH₂)₃C₂F₅.
 14. A compound accordingto claim 1, in which Y is the side chain (CH₂)₅N(R⁵)(CHR⁶)CH₂S(CH₂)₃C₂F₅with R⁵+R⁶ being —(CH₂)₃.
 15. A compound according to claim 1, whereinR¹ and R² are each independently H, OH, C₁-C₁₀ alkoxy, C₁-C₁₀alkanoyloxy, or C₇-C₁₅ aroyloxy.
 16. A compound according to claim 1,wherein R¹ and R² are each independently H, OH, alkoxy, methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy,isopentoxy, neopentoxy, heptyloxy, hexyloxy, decyloxy, formyl, acetyl,propionyl, isopropionyl or benzoyl.
 17. A method for performing male orfemale hormone replacement therapy in a patient comprising administeringto said patient an effective amount of a compound according to claim 1.18. A method for the treatment of dysmenorrhea in a patient comprisingadministering to said patient an effective amount of a compoundaccording to claim
 1. 19. A method for the treatment of dysfunctionaluterine bleeding in a patient comprising administering to said patientan effective amount of a compound according to claim
 1. 20. A method forthe treatment of cardiovascular disease in a patient comprisingadministering to said an effective amount of a compound according toclaim
 1. 21. A method for the treatment of osteoporosis in a patientcomprising administering to said patient an effective amount of acompound according to claim
 1. 22. A method for the prevention of boneloss in a postmenopausal patient who has had a hysterectomy or who hasbeen treated with a LHRH agonist or a LHRH antagonist, said methodcomprising administering to said patient an effective amount of acompound according to claim
 1. 23. A method for inhibition of spermaticmaturation in a patient comprising administering to said patient aneffective amount of a compound according to claim
 1. 24. A method forthe treatment of endometriosis in a patient comprising administering tosaid patient an effective amount of a compound according to claim
 1. 25.A method for the treatment of myomas, endometriosis, or both in apatient comprising administering to said patient an effective amount ofa LHRH analogue and an effective amount of a compound according toclaim
 1. 26. A method for the treating hormone-dependent tumors in apatient, comprising administering to said patient an effective amount ofa compound according to claim
 1. 27. A method according to claim 26,wherein the hormone-dependent tumors are breast cancer tumors.
 28. Amethod for the treatment of prostatic disease in a patient comprisingadministering to said patient an effective amount of a compoundaccording to claim
 1. 29. A method according to claim 17, wherein saidcompound is administered in an amount of 0.01-10 mg/kg of body weightper day.
 30. A method according to claim 17, wherein said compound isadministered in an amount of 0.1-5 mg/kg of body weight per day.
 31. Amethod according to claim 17, wherein said compound is administered in adaily dosage of 0.8-800 mg.
 32. A method according to claim 17, whereinsaid compound is administered in a daily dosage of 8-400 mg.
 33. Amethod according to claim 17, wherein said compound is administered in adosage unit containing 0.4-400 mg of said compound.